Fatty acid analogs and prodrugs

ABSTRACT

Novel derivatives of fatty acid analogs that have from one to three heteroatoms in the fatty acid moiety which can be oxygen, sulfur or nitrogen, are disclosed in which the carboxy-terminus has been modified to form various amides, esters, ketones, alcohols, alcohol esters and nitriles thereof. 
     These compounds are useful as substrates for N-myristoyltransferase (NMT) and/or its acyl coenzyme, and as anti-viral and anti-fungal agents or pro-drugs of such agents. Illustrative of the disclosed compounds are fatty acid amino acid analogs of the structure ##STR1## in which X is the ethyl or t-butyl ester of an amino acid such as Gly, L-Ala, L-Ile, L-Phe, L-Trp, L-Thr or an amide such as NHCH 2  C 6  H 5  or NH(CH 2 ) 2  C 6  H 5 .

CROSS-REFERENCE TO RELATED APPLICATION

This is a continuation of application Ser. No. 08/410,450, filed Mar.24, 1995, now U.S. Pat No. 5,599,947, which is a CIP of application Ser.No. 08/004,370, filed Jan. 14, 1993 now abandoned.

BACKGROUND OF THE INVENTION

This invention relates to novel compounds and, more particularly, tonovel derivatives of fatty acid analogs that have from one to threeheteroatoms in the fatty acid moiety which can be oxygen, sulfur ornitrogen, and in which the carboxy-terminus has been modified to form,e.g., various amides, esters, ketones, alcohols, alcohol esters andnitriles thereof.

These novel compounds are useful as anti-viral and anti-fungal agents orpro-drugs of such agents and are particularly useful as inhibitors ofretroviruses, especially lentiviruses such as the human immunodeficiencyvirus (HIV).

The fatty acid acylation of specific eukaryotic proteins is awell-established process. See, e.g., the review article by Towler etal., Ann. Rev. Biochem. 57, 69-99 (1988), and references cited therein.

Fatty acid analogs containing heteroatom replacements of methylenegroups in the fatty acid chain by oxygen, sulfur and nitrogen have beenshown to have various anti-viral and antifungal activity. See, e.g.,

Bryant et al., Proc. Natl. Acad. Sci. USA 86, 8655-8659 (1989);

Bryant and Rather, Proc. Natl. Acad. Sci. USA 87, 523-527 (1991);

Doering et al., Science 252, 1851-1854 (1991);

Bryant et al., Proc. Natl. Acad. Sci. USA 88, 2055-2059(1991);

and Devadas et al., J. Biol. Chem. 267, 7224-7239 (1992).

See also,

U.S. Pat. Nos. 5,073,571; 5,082,967; 5,151,445;

and EPO published patent applications EP 327,523 and EP 480,901.

In French Patent application 2,657,259, N-myristoyl-(S)-phenylalanine isdisclosed as an inhibitor of NMT for treatment of cancer and retroviralinfection, e.g. AIDS. Antiviral myristoyl-glycine is disclosed inJapanese Patent applications 62-126384 and 62-255810. These reportedmyristoylamino acids do not contain heteroatoms in the myristic acidmoiety.

BRIEF DESCRIPTION OF THE INVENTION

In accordance with the present invention, novel derivatives of fattyacid analogs that have from one to three heteroatoms in the fatty acidmoiety which can be oxygen, sulfur or nitrogen, are provided in whichthe carboxy-terminus is modified to form various amides, esters,ketones, alcohols, alcohol esters and nitriles thereof. These novelcompounds can be represented by the following general structural FormulaI:

General Structure

    A-Alk.sub.1 -B-Alk.sub.2 -C-Alk.sub.3 (W)-Y                (I)

wherein

A=H, N₃, CN, SH, OH, tetrazolyl, triazoyl,

B=O, NR₈, S(O)_(m), lower alkylene,

C=O, NR₈, S(O)_(m), lower alkylene,

Alk₁ =lower alkylene, branched or unbranched,

Alk₂ =lower alkylene, branched or unbranched,

Alk₃ =lower alkylene, branched or unbranched or W substituted loweralkylene,

Y=COCl, CONRR₁, CO-AA-OR₃, CONR₂ -AA-OR₃, CO₂ R₄, COR₅, CN, CH₂ OH,CSNH₂, CH₂ O₂ CR₆, ##STR2## and wherein m=0-2,

W=OZ, halogen, NR₈, alkyl, aryl, arylalkyl,

Z=H, alkanoyl, aroyl, arylalkanoyl,

wherein

R=H, alkyl, aryl, arylalkyl,

R₁ =H, alkyl, aryl, arylalkyl,

R₂ =H, alkyl, aryl, arylalkyl,

R₃ =H, alkyl, aryl, arylalkyl,

R₄ =H, alkyl, aryl, arylalkyl,

R₅ =alkyl, aryl, arylalkyl,

R₆ =alkyl, aryl, arylalkyl,

R₇ =H, alkyl, aryl, arylalkyl, and

R₈ =H, alkyl, aryl, arylalkyl,

AA=D, L, DL or achiral amino acid side chain, and provided that whenY=CO₂ R₄, R₄ is aryl or arylalkyl, and provided further that at leastone of B or C contains a N, O or S heteroatom.

In the foregoing general structural Formula I, the lower alkylene groupsin each of B, C, Alk₁, Alk₂ and Alk₃ can independently contain from oneto about 6 carbon atoms but the total number of carbon atoms in thefatty acid chain when B and C are each alkylene preferably should be 11or 12.

When B and/or C are any of the heteroatoms O, S(O)_(m) and NR₈, each ofthese heteroatoms replaces a methylene group in the fatty acid chain.

The alkyl moieties in any of the R to R₈ groups preferably contain from1 to 12 carbon atoms whereas the aryl and arylalkyl moieties in any ofthe R to R₈ groups preferably contain from 6 to 12 carbon atoms.

The alkyl and alkylene groups can be saturated or unsaturated. By theterm (W) is meant a side chain on Alk₃. The preferred halogens of thisside chain are chlorine, bromine and fluorine.

Three preferred groups of compounds of the above general structuralFormula I are as follows:

A compound of Formula I in which

A=H,

Alk₁ =CH₂, (GROUP A)

B=O and

Alk₂ -C-Alk₃ (W)=(CH₂)₁₁ ;

A compound of Formula I in which

A=H,

Alk₁ =CH₂, (GROUP B)

B=O,

Alk₂ =(CH₂)₇,

C=O and

Alk₃ (W)=(CH₂)₃.

A compound of Formula I in which

A=H,

Alk₁ =(CH₂)₁₀, (GROUP C)

B=O and

Alk₂ -C-Alk₃ (W)=(CH₂)₂.

When Y contains a AA-OR₃ group, AA can be a D, L, DL or achiral naturalor unnatural alpha-amino acid or natural or unnatural amino acid withthe basic amine displaced further from the ##STR3##

These amino acids can be, for example, any of the approximately 20natural amino acids that commonly occur in proteins as follows:

    ______________________________________                                        L-Alanine L-Asparagine                                                                             L-Arginine  L-Aspartic acid                              L-Cystine L-Cysteine L-Glutamic acid                                                                           L-Glutamine                                  Glycine   L-Histidine                                                                              Hydroxylysine                                                                             4-Hydroxyl-                                  L-Isoleucine                                                                            L-Leucine  L-Lysine    L-proline                                    L-Phenylalanine                                                                         L-Proline  L-Serine    L-Methionine                                 L-Thyroxine                                                                             L-Tryptophan                                                                             L-Tyrosine  L-Threonine                                                                   L-Valine                                     ______________________________________                                    

Amino acids have a primary amino function and a carboxyl function joinedto the same carbon atom. Thus, they are called α-amino acids and arederivatives of the general structure NH₂ --CHR--COOH, in which R can beH or various aliphatic and/or aryl groups. Two exceptions in this listof natural amino acids are L-proline and 4-hydroxyl-L-proline, which areα-imino acids.

β-Amino acids also are commonly known. They have an amino group attachedto the carbon one removed from the carboxyl carbon. The nitrogen atom ofβ-amino acids, as in the case with α-amino acids, can be alkylated.

These naturally occurring and commonly known amino acids can beclassified into various groups, illustrated hereinafter such as, e.g.,those which have:

(1) aliphatic side chains,

(2) hydroxylic side chains,

(3) carboxylic side chains and their amides,

(4) basic side chains,

(5) aromatic side chains,

(6) sulfur-containing side chains, and

(7) the imino acids.

These amino acids can also be employed herein in the D-configuration asillustrated, for example, by the following:

D-Alanine

D-Isoleucine

D-Phenylalanine

D-Glutamic acid

D-Lysine

D-Tryptophan

D-Threonine

Likewise, DL-mixtures of any of these amino acids can be used herein.

Less common amino acids which can be used herein are illustrated by:

β-Alanine (3-Aminopropionic acid)

Homocystine (4,4'-Dithiobis 2-amino-butanoic acid !)

Norleucine (2-Aminohexanoic acid )

Norvaline (2-Aminovaleric acid)

Ornithine (2,5-Diaminopentanoic acid)

Penicillamine (3-Mercapto-D-valine )

Phenylglycine and N-Phenylglycine

Sarcosine (N-Methylglycine)

Taurine (2-Aminoethanesulfonic acid )

All of the illustrative amino acids are commercially available and/orcan be readily isolated or synthesized by well-known published methods.See, e.g., Williams, Synthesis of Optically Active α-Amino Acids, Vol. 7in Organic Chemistry Series, Eds. Baldwin and Magnus, Pergammon Press,1989. Their chemical structures are also well known as can be seen,e.g., from conventional texts such as Mahler & Cordes, BiologicalChemistry, Harper & Row, 1966, pp. 8-15; Fieser and Fieser, AdvancedOrganic Chemistry, Reinhold Publ. Corp., 1962, pp. 1014-1034; and TheMerck Index, Eleventh Edition, 1989.

In the general structure of the compounds of Formula I, the N-terminusof the amino acid moiety is bound to the carboxy-terminus of theheteroatom-containing fatty acid moiety. The carboxy-terminus of theamino acid moiety, in turn, is derivatized to form various amides,esters, ketones, alcohols, alcohol esters and nitriles. The compounds ofFormula I which thus contain an amino acid moiety can be represented bythe following structural Formula II: ##STR4## wherein: FA is aheteroatom-containing fatty acid moiety selected from the groupconsisting of CH₃ O(CH₂)₁₁ -and CH₃ (CH₂)₉ O(CH₂)₂ -;

f is zero or one;

X is selected from the group consisting of OH, O-alkyl having from oneto six carbon atoms, and N(R₁)R in which R and R₁ are H or alkyl havingfrom one to six carbon atoms or arylalkyl having from one to eightcarbon atoms;

D is selected from the group consisting of H, alkyl, aryl, arylalkyl andcarboxyalkyl;

E is selected from the group consisting of H, alkyl, aryl, arylalkyl,heteroarylalkyl, arylalkyl substituted with OH or halogen, benzofusedheteroarylalkyl, hydroxyalkyl, alkoxy-alkyl, arylalkoxyalkyl, thioalkyl,alkylthioalkyl, arylalkylthioalkyl, carboxyalkyl, carboxamidoalkyl,aminoalkyl, aminohydroxyalkyl, diaminoalkyl and guanidinoalkyl;

and in which the number of carbon atoms in each of D and E is from zeroto eight.

In the above Formula II, the E groups are illustrated hereinbelow withamino acids as follows:

H is illustrated in glycine;

Alkyl is illustrated in alanine, isoleucine, leucine and valine;

Aryl is illustrated in phenylglycine;

Arylalkyl is illustrated in phenylalanine;

Arylalkyl substituted with OH or halogen is illustrated in tyrosine andfluorophenylalanine;

Heteroarylalkyl (including benzofused) is illustrated in histidine andtryptophane;

Hydroxyalkyl is illustrated in serine and threonine;

Alkoxyalkyl and arylalkoxyalkyl are illustrated in O-methylserine,O-benzylserine and O-benzylthreonine;

Thioalkyl is illustrated in cysteine and its disulfide dimer cystine;

Alkylthioalkyl and arylalkylthioalkyl are illustrated in methionine andS-benzylcysteine;

Carboxyalkyl is illustrated in aspartic acid and glutamic acid;

Carboxamidoalkyl is illustrated in glutamine and asparagine;

Aminoalkyl is illustrated in lysine, N-(O-benzyl)-carbamoyllysine andN-(O-orthochlorobenzyl)-carbamoyllysine;

Amino-hydroxyalkyl is illustrated in hydroxylysine;

Diaminoalkyl is illustrated in aminolysine and ornithine; and

Guanidinoalkyl is illustrated by arginine andN'-toluenesulfonylarginine.

In the above Formula II, the D groups are illustrated hereinbelow withamino acids as follows:

H is illustrated in glycine (Gly);

Alkyl is illustrated in N-(CH₃)-Gly-; Aryl is illustrated in N-(Ph)-Gly;

Arylalkyl is illustrated in N-(Bn)-Gly; and

Carboxyalkyl is illustrated in N-(Gly-OEt)-Gly;

wherein Ph is phenyl and Bn in benzyl.

For convenience in depicting representative compounds within the scopeof Formula II, the amino acid moiety, R, can be shown by theconventional three letter abbreviations of the amino acid as follows:

    ______________________________________                                        Abbreviated Designation                                                                             Amino Acid                                              ______________________________________                                        Ala                   Alanine                                                 Cys                   Cysteine                                                Asp                   Aspartic acid                                           Glu                   Glutamic acid                                           Phe                   Phenylalanine                                           Gly                   Glycine                                                 His                   Histidine                                               Ile                   Isoleucine                                              Lys                   Lysine                                                  Leu                   Leucine                                                 Met                   Methionine                                              Asn                   Asparagine                                              Pro                   Proline                                                 Gln                   Glutamine                                               Arg                   Arginine                                                Ser                   Serine                                                  Thr                   Threonine                                               Val                   Valine                                                  Trp                   Tryptophan                                              Tyr                   Tyrosine                                                ______________________________________                                    

It will be appreciated that the novel compounds of the invention can beprepared and used in the free amine or free acid forms or as saltsthereof. Amine salts can be, e.g., hydrochloride, trifluoracetate ortosylate salts and the like.

Carboxylic acid salts can be, e.g., sodium, potassium, calcium,ammonium, mono- di- or tri-substituted or quaternary ammonium salts andthe like.

Preferred compounds of Formula II have amino acid moieties convenientlyillustrated by the following groups:

Gly--OH,

Gly-OEt

Gly-Ot-Bu,

NH(CH₂)₂ CO₂ Et,

Gly-Gly-OEt,

N-(Gly-OEt)-Gly-OEt,

N-(CH₃)-Gly-OEt,

N-(Ph)-Gly-OEt,

N-(Bn)-Gly-OEt,

(±)--NHCH₂ CH(CH₃)CO₂ Et,

L-Ala-OEt,

L-NHCH₂ CH(CH₃)CO₂ Et,

D-Ala-OEt,

L-lle-OEt,

D-lle-OEt,

L-Phe-OH,

NHCH₂ CH(CH₂ Bn)CO₂ Et,

L-Phe-OEt,

L-Phe-O-t-Bu,

D-Phe--OH,

D-Phe-O-Et,

D-Phe-O-t-Bu,

L-Glu(OBzl)-OEt,

D-Glu(OBzl)-OEt,

D-Lys(Cl-Z)-OEt,

L-Lys(Cl-Z)-OEt,

L-Trp-OEt,

D-Trp-OEt,

L-Thr(OBzl)-OEt, and

D-Thr(OBzl)-OEt.

In accordance with another embodiment of the invention, certain otherillustrative compounds of Formula I can be represented by the followingstructural Formulas IIIa and IIIb: ##STR5## wherein: FA is aheteroatom-containing fatty acid moiety selected from the groupconsisting of CH₃ O(CH₂)₁₁ -and CH₃ (CH₂)₉ O(CH₂)₂ -;

X is selected from the group consisting of amido, monoalkyl-amido,dialkyl-amido, monoaryl-amido, monoaryl-amido substituted with OH orhalogen, diaryl-amido, and diaryl-amido substituted with OH or halogen;

and in which the number of carbon atoms in alkyl are from one to eightand the number of carbon atoms in aryl is six.

In the above Formulas IIIa and IIIb, X is illustrated hereinbelow withthe following groups: ##STR6##

In still another embodiment of the invention, other illustrativecompounds of Formula I can be represented by the following structuralFormula IV:

    FA-X                                                       (IV)

wherein:

FA is a heteroatom-containing fatty acid moiety selected from the groupconsisting of CH₃ O(CH₂)₁₁ -and

CH₃ (CH₂)₉ O(CH₂)₂ -;

X is selected from the group consisting of cyano, tetrazole,N-alkyltetrazole and N-arylalkyltetrazole;

and in which the number of carbon atoms in alkyl is from one to eight,and the number of carbon atoms in aryl is six.

In the above Formula IV, X is illustrated herein below with thefollowing groups: ##STR7##

Other preferred compounds of the invention are conveniently representedby the following structural Formula V:

    CH.sub.3 O(CH.sub.2).sub.7 --X--(CH.sub.2).sub.2 --Y       (V)

wherein X is CH₂ or O, and Y is COCH₃ or CH₂ OH.

Still other preferred compounds of the invention are convenientlyrepresented by the following structural Formula VI:

    CH.sub.3 (CH.sub.2).sub.9 O(CH.sub.2).sub.2 --X            (VI)

wherein X is selected from the group consisting of

CN,

CONEt₂,

CONHCH₂ Ph,

CO-Gly-OEt,

CO-D-Phe-OEt, and

CO-L-Phe-OEt.

Preferred compounds included within the scope of the foregoingstructural formulas are the following: ##STR8##

The novel compounds of this invention can be synthesized by variousmethods of preparation as illustrated by the following generic ReactionSchemes 1 to 18. ##STR9## Reaction Scheme 1 illustrates the genericpreparation of fatty acids of Formula I in which A, B, C, Alk₁, Alk₂,Alk₃ and W are defined as hereinbefore from the reaction of alcohols andω-halo alkenes via a nucleophilic displacement followed by subsequentoxidative cleavage of the vinyl moiety.

Accordingly, alcohol (1) is treated with base (e.g. sodium hydride,n-butyllithium or potassium t-butoxide) in an organic solvent such astetrahydrofuran (THF) or diethylether to form the alkoxide which is thencoupled with an ω-halo alkene to form the chain extended alkene (2)which is then converted to the fatty acid (I) by oxidative cleavage ofthe alkene moiety using an oxidizing agent (e.g. KMnO₄, H₂ CrO₇ or RuCl₃/NalO₄) in a biphasic solvent system to give the fatty acid (I).

Reaction Scheme 2 illustratively shows the preparation of 4-(7-methoxyheptyl)-oxy!butanoic acid wherein 7-methoxyheptan-1-ol(3) istreated with sodium hydride in tetrahydrofuran (THF) followed by theaddition of 5-bromopentene to form 6,14-dioxapentadecan-1-ene(4) whichin turn is treated with ruthenium(III) chloride hydrate (RuCl₃ xH₂ O)and sodium periodate (NaIO₄) in a 1:1.5:1 mixture of acetonitrile, waterand carbon tetrachloride to form a mixture of aldehyde and carboxylicacid which is subsequently treated with Jones Reagent (H₂ CrO₇ /acetone)to give the desired fatty acid (5).

Reaction Scheme 3 illustrates the generic preparation of fatty acidamide analogs of Formula 7 in which A, B, C, Alk₁, Alk₂, Alk₃, W, R andR₁ are defined as hereinbefore from carboxylic acids of Formula I byreacting the fatty acid analog with an inorganic acid halide (e.g. PCl₅,PCl₃, SOCl₂) or acyl halides e.g. (COCl)₂ ! in an organic solvent suchas methylene chloride or toluene to form the corresponding fatty acidchloride (6) followed by coupling with an appropriate primary orsecondary organic amine (e.g. benzylamine, diethylamino, morpholine) inan organic solvent such as methylene chloride, tetrahydrofuran (THF), oracetonitrile to give the fatty acid amide analog (7).

Reaction Scheme 4 illustratively shows the preparation of12-methoxy-N-(phenyl-methyl)dodecanamide wherein 12-methoxydodecanoicacid (8) is treated with oxalyl chloride in anhydrous toluene to form12-methoxydodecanoyl chloride (9) which in turn reacts with benzylaminein methylene chloride to give the desired fatty acid amide (10).

Reaction Scheme 5 illustrates the generic preparation of fatty acidamino acid analogs of Formula 14 in which A, B, C, Alk₁, Alk₂, Alk₃, W,R₂, R₃ and AA are defined as hereinbefore from a protected amino acid(11) where P is a standard amine protecting group (e.g. tert-butyloxy orbenzylcarboxy) well known to one skilled in the art (see T. W. Greeneand P. G. M. Wuts, "Protective Groups in Organic Synthesis", John Wiley& Sons, 1991).

The compound of Formula 11 is converted by either (i) acid catalyzedesterification or (ii) SN2 alkylation of the corresponding carboxylatesalt to form the corresponding amino acid ester (12) which is thensubjected to deprotection of the amine protecting group by either (i)acid hydrolysis (e.g. trifluoroacetic acid or hydrochloric acid) in anorganic solvent such as methylene chloride or dioxane or (ii) bycatalytic hydrogenolysis to form the amine (13) as either the ammoniumsalt or the free base, respectively. Treatment of the amine or itsammonium salt (13) with a fatty acid chloride (8) in an organic solventsuch as methylene chloride, tetrahydrofuran (THF) or acetonitrile givesthe fatty acid amino acid ester analog (14) which is converted to thefatty acid amino acid analog (15) by acid or base catalyzed hydrolysis.

Reaction Scheme 6 illustratively shows the preparation ofN-(12-methoxy-1-oxododecyl)-D-alanine, ethyl ester whereinN-(t-butyloxycarbonyl)-D-alanine (16) is treated withtetramethylammonium hydroxide pentahydrate in acetonitrile followed bythe addition of ethyl iodide to form N-(t-butyloxycarbonyl)-D-alanine,ethyl ester (17) which in turn reacts with trifluoroacetic acid inmethylene chloride to give the trifluoroacetate salt of D-alanine ethylester (18) which, when treated with 2-methoxydodecanoyl chloride (9) inmethylene chloride, gives the desired fatty acid amino ester (19).

Reaction Scheme 7 illustrates the preparation ofN-(12-methoxy-1-oxododecyl)-glycine (21) whereinN-(12-methoxy-1-oxododecyl)-glycine 1,1-dimethylethyl ester (20) istreated with hydrochloric acid in dioxane to give the desired fatty acidamino acid (21).

Reaction Scheme 8 illustrates the generic preparation of fatty acidesters of Formula 22 in which A, B, C, Alk₁, Alk₂, Alk₃, W and R4 aredefined as hereinbefore by converting carboxylic acids of Formula I byeither (i) acid catalyzed esterification or (ii) SN2 alkylation of thecorresponding carboxylate salt to form the corresponding fatty acidester (22).

Reaction Scheme 9 illustratively shows the preparation of ethyl12-methoxydodecanoate wherein 12-methoxydodecanoic acid (8) is treatedwith tetramethylammonium hydroxide pentahydrate in acetonitrile followedby the addition of ethyl iodide to give the desired fatty acid ester(23).

Reaction Scheme 10 illustrates the generic preparation of ketones ofFormula 26 in which A, B, C, Alk₁, Alk₂, Alk₃, W and R₅ are defined ashereinbefore by reacting the fatty acid amides of Formula 24 withdehydrating agents (e.g. P₂ O₅, SOCl₂, PCl₃, PCl₅, TsCl) in an organicsolvent such as toluene or pyridine to give the corresponding nitrile(25) followed by treatment with an organometallic reagent, e.g. aGrignard reagent, and subsequent hydrolysis of the intermediate ketiminesalt to form the ketone (26).

Reaction Scheme 11 illustratively shows the preparation of13-methoxy-2-tridecanone (29) wherein 12-methoxydodecanamide (27) istreated with p-toluenesulfonyl chloride in pyridine to give the nitrile(28) which is first treated with methylmagnesium chloride indiethylether followed by aqueous HCl to give the desired ketone (29).

Reaction Scheme 12 illustrates the generic preparation of alcohols ofFormula 30 in which A, B, C, Alk₁, Alk₂, Alk₃, and W are defined ashereinbefore by treating the carboxylic acid (I) with a reducing agent(e.g. borane, lithium aluminum hydride) in an organic solvent such asdiethylether, tetrahydrofuran (THF) or dioxane followed by hydrolysisunder acidic or basic conditions to afford the alcohol (32).

Reaction Scheme 13 illustratively shows the preparation of ethyl12-methoxy-dodecanoate wherein 12-methoxydodecanoic acid (8) is treatedwith borane in tetrahydrofuran followed by hydrolysis with aqueouspotassium carbonate to give the desired alcohol (31).

Reaction Scheme 14 illustrates the generic preparation of thioamides ofFormula 32 in which A, B, C, Alk₁, Alk₂, Alk₃, W, R₁ and R are definedas hereinbefore by subjecting the fatty acid amide of Formula 7 to athionation reaction (P₂ S₅, S₈, Lawesson's Reagent) in an organicsolvent such as tetrahydrofuran (THF), methylene chloride or dioxane toform the thioamide (32).

Reaction Scheme 15 illustratively shows the preparation of12-methoxydodecanethioamide (33) wherein 12-methoxydodecanamide (27) istreated with Lawesson's Reagent in tetrahydrofuran (THF) to give thedesired thioamide (33).

Reaction Scheme 16 illustrates the generic preparation of alkylatedtetrazoles of Formula 35 in which A, B, C, Alk₁, Alk₂, Alk₃, W, and R₇are defined as hereinbefore by converting the fatty acid nitrile (25)into the tautomeric free tetrazole (34) using an azide reagent (e.g. NH₄Cl/NaN₃, Me₃ SnN₃ or Bu₃ SnCl/NaN₃ /LiCl) which is then alkylated with avariety of electrophiles (e.g. ethyl iodide or benzyl bromide) to givethe alkylated tetrazole (35).

Reaction Scheme 17 illustratively shows the preparation of5-(11-methoxyundecyl)-1H-tetrazole (36) wherein12-methoxydodecanenitrile (28) is treated with a mixture of sodiumazide, tri-n-butyltin chloride and lithium chloride toluene to give thedesired tetrazole (36).

Reaction Scheme 18 illustratively shows the preparation of bothregioisomers of ethyl-5-(11-methoxyundecyl)-H-tetrazole (37 and 38)wherein 5-(11-methoxyundecyl)-1H-tetrazole (36) is treated with sodiumhydride in dimethylformamide followed by the addition of ethyl iodide togive the desired alkylated tetrazoles (37 and 38).

The general methods outlined in the foregoing Reaction Schemes arereadily adaptable to variations by persons skilled in the art. Forexample, it is well known that one electrophilic group can besubstituted for another electrophilic group and one nucleophilic groupcan be substituted for another nucleophilic group.

More specifically, nucleophiles such as sulfhydryl, substituted amino oramino groups can be substituted for hydroxyl groups. Likewise,electrophiles such as halogens, sulfonate esters, trifluoroacetateesters and the like can be employed interchangeably. The order ofconnection of, for example, A, Alk₁, Alk₂, Alk₃ can be varied.Protecting groups can be employed if desired.

Examples of protecting groups are tert-butyl esters, isoxazoles,trifluoroacetates, tetrahydropyranyl ethers and the like as referred toin the Green and Wuts text cited hereinbefore.

Likewise, one skilled in the art can readily replace other componentsmentioned in the foregoing Reaction Schemes. For example, one can usenon-protic or dipolar aprotic solvents such as xylene, dimethoxyethane,diethoxyethane, sulfolane, dimethylformamide, dimethylsulfoxide,dioxane, furan, thiophene, dimethyl-acetamide, heptane, tetramethylureaand the like. Alternative protic solvents include methanol, water,isopropanol, tert-butanol, ethoxyethanol and the like which may replacethe exemplified protic solvents when the solvent is not also used as aspecific reagent.

The preferred temperature for the reactions disclosed in the ReactionSchemes and Examples is room temperature unless otherwise specified;however, in some cases temperatures between -78° and solvent reflux maybe used. Many Examples disclosed require a dry atmosphere to obtain thebest results or for safety reasons. An inert atmosphere may also be usedsuch as that obtained using an atmosphere of argon or nitrogen.

Alternative non-reagent amine bases for the disclosed Reaction Schemesinclude, for example, N-methyl-morpholine, diazabicyclononane andN,N-dimethylaminopyridine (DMAP) and the like. Mineral bases can includesodium carbonate, sodium bicarbonate, potassium hydroxide, sodiumhydroxide, lithium hydroxide, lithium carbonate, calcium carbonate,barium hydroxide and aluminum hydroxide or oxide.

Hydride bases can include lithium hydride, calcium hydride, potassiumhydride and the like as well as organometallic bases such as tert-butyllithium, lithium acetylide, ethyl magnesium bromide, isopropyl magnesiumchloride and the like. Other useful acids can include, for example,hydrogen bromide (hydrobromic acid), sulfuric acid, phosphoric acid,potassium phosphate, toluene sulfonic acid, benzene sulfonic acid,methane sulfonic acid, benzyl phosphoric acid, trifluromethyl sulfonicacid, nitrobenzoic acid, trichloroacetic acid and acetic acid as well asLewis acids such as aluminum chloride, borontrifluoride, tin chlorides,titanium halides and the like.

Hydrogenation catalysts for use in the above Reaction Schemes caninclude, for example, palladium chloride, palladium metal of variousmesh sizes, palladium on barium sulfate, nickel, platinum and platinumoxide with hydrogen gas as well as with hydrogen transfer reagents suchas cyclohexadiene and cyclohexene used with or without pressures greaterthan atmospheric pressure.

The sulfoxides of this invention are readily prepared by treating theappropriate sulfide with an oxidizing agent and the sulfones can beprepared either directly from the sulfide or from the sulfoxide.Suitable oxidizing agents include, but are not limited to, hydrogenperoxide, metal periodates, periodic acid, peracetic acid,meta-chloroperbenzoic acid, tert-butyl hypochlorite or optically activeagents that induce optical activity in the product such as percamphoricacid. These oxidations can be carried out at temperatures ranging from-80° C. to solvent reflux but the preferred temperatures are between-20° and 35° C.

Although specific methods of production are described herein, it will beappreciated that the novel antiviral compounds claimed herein are notlimited to any particular method of production.

In standard biological tests, the novel compounds of this invention havebeen shown to have inhibitory activity against the humanimmunodeficiency virus (HIV), which is a lentivirus.

Inhibitory activity against HIV-1 was shown by tests involving platingof susceptible human host cells which are syncytium-sensitive with andwithout virus in microculture plates, adding various concentrations ofthe test compound, incubating the plates for 7 to 9 days (during whichtime infected, non-drug treated control cells are largely or totallydestroyed by the virus), and then determining the remaining number ofviable cells with a colorometric endpoint.

The following Examples will further illustrate the invention in greaterdetail, although it will be understood that the invention is not limitedto these specific Examples or the specific details described therein.

From these specific examples and the general disclosure hereinbefore,the person skilled in the art will readily appreciate and recognizenumerous other examples within the scope of the appended claims withoutdeparting from the spirit and scope of the claims appended below.

EXAMPLE 1 ##STR10## 12-Methoxydodecanoic Acid

12-Bromoundecanoic acid (20 g, 72 mmol) in 600 mL of methanol was addeddropwise to a solution of sodium methoxide in methanol (50 mL, 4.4M) at0° C. After stirring at room temperature for 2 hours, the resultingcloudy solution was refluxed for 46 hours. The solvent was removed byrotary evaporator and the residue partioned between diethyl ether andwater. The aqueous phase was acidified to pH 1 with 6N HCl and extractedwith two portions of diethyl ether. The combined organic extracts werewashed with brine, dried over magnesium sulfate, filtered andconcentrated to give the title compound (16.1 g) as a white solid, m.p.45.9°-48.0° C. (DSC). The structure was supported by NMR, infraredspectroscopy, elemental analysis and mass spectroscopy.

Analysis for C₁₃ H₂₆ O₃ (MW 230.4): Calcd.: C, 67.79; H, 11.38.

Found: C, 67.62; H, 11.53.

EXAMPLE 2 CH₃ O(CH₂)₆ COOH

7-Methoxyheptanoic Acid

The title compound was prepared by the method of Example 1 using7-bromoheptanoic acid (50 g, 239 mmol) instead of 12-bromoundecanoicacid and dimethylformamide (300 mL) instead of methanol as the solvent.Concentration afforded the title compound (30 g) as a pale yellow liquidand the structure verified by NMR.

EXAMPLE 3 CH₃ O(CH₂)₇ OH

7-Methoxy-1-heptanol

To a solution of the title product of Example 2 (18.3 g, 114 mmol) in 60mL of tetrahydrofuran at 0° C. was added dropwise a solution of boranein tetrahydrofuran (175 mL, 1M). After stirring at room temperature for3 days, 300 mL of water was added followed by solid K₂ CO₃ (31.7 g, 229mmol). The layers were separated and the aqueous phase extracted withthree portions of diethyl ether. The combined organic extracts werewashed with brine, dried over magnesium sulfate, filtered andconcentrated. The crude product was purified by distillation at reducedpressure (8 mm Hg) to give the title compound (12 g), b.p. 107°-110° C.The structure was verified by NMR.

EXAMPLE 4 ##STR11## 1-Methoxy-7-(4-pentenyloxy)heptane

Sodium hydride (665 mg, 17 mmol, washed three times with hexane) wastreated with the title product of Example 3 (2.0 g, 14 mmol) in 90 mL oftetrahydrofuran at reflux for one hour. A solution of 5-bromopentene(2.0 g, 14 mmol) in 50 mL of tetrahydrofuran was added dropwise andrefluxing continued for 20 hours. After cooling to room temperature, 50mL of water was added, the layers separated and the aqueous phase wasextracted with two portions of ethyl acetate. The combined organicextracts were washed with brine, dried over magnesium sulfate, filteredand concentrated. Chromatography of the crude residue on silica gelusing 50-50 ethyl acetate-heptane as eluant gave the title compound (485mg) as a yellow oil and the structure verified by NMR.

EXAMPLE 5 ##STR12## 4- (7-Methoxyheptyl)oxy!butanoic Acid

To a heterogeneous solution of the title product of Example 4 (319 mg,1.5 mmol) in 3 mL of carbon tetrachloride, 3 mL of acetonitrile and 4.5mL of water was added sodium metaperiodate (1.4 g, 6.4 mmol) followed byruthenium trichloride hydrate (9 mg, 40 mol). After stirring vigorouslyfor 3 hours at room temperature, the mixture was diluted with methylenechloride, the layers separated and the aqueous phase extracted with twoportions of methylene chloride. The combined organic extracts werewashed with brine, dried over magnesium sulfate, filtered andconcentrated affording a mixture of oxidized products. To this mixturein 5 mL of acetone was added Jones Reagent (8N H₂ CrO₇) dropwise untilthe usual orange color persisted. The reaction was partioned betweendiethyl ether and water, the layers separated and the aqueous phaseextracted with two portions of diethyl ether. The combined organicextracts were washed with brine, dried over magnesium sulfate, filteredand concentrated. Chromatography of the crude residue on silica gelusing 30-70 ethyl acetate-hexane as eluant gave the title compound (217mg) as a yellow oil. The structure was supported by NMR, infraredspectroscopy, elemental analysis and mass spectroscopy.

Analysis for C₁₂ H₂₄ O₄ (MW 232.3): Calcd.: C, 62.04; H, 10.41.

Found: C, 61.79; H, 10.73.

EXAMPLE 6 CH₃ (CH₂)₉ O(CH₂)₂ CN.tbd.N

3-(Decyloxy)propanenitrile

Sodium hydride (200 mg, 5 mmol; washed three times with hexane) wastreated with 1-decanol (12 mL, 63 mmol) for 1 hour at room temperature.Acrylonitrile (10 mL, 152 mmol) was added dropwise and the resultingpaste warmed to 60 ° C. for 2 hours. After cooling to room temperature,the paste was dissolved in diethyl ether and washed with copious water,one portion of brine, dried over magnesium sulfate, filtered andconcentrated. Chromatography of the crude residue on silica gel using25-75 ethyl acetate-hexane as eluant gave the title compound (5.5 g) asa water-white liquid. The structure was supported by NMR, infraredspectroscopy, elemental analysis and mass spectroscopy.

Analysis for C₁₃ H₂₅ NO (MW 211.4): Calcd.: C, 73.88; H, 11.92; N, 6.63.

Found: C, 74.00; H, 11.84; N, 6.49.

EXAMPLE 7 ##STR13## 3-(Decyloxy)propanoic Acid

To a suspension of the title product of Example 6 (3.8 g, 18 mmol) in140 mL of concentrated HCl was added 25 mL of glacial HOAc and theresulting mixture refluxed for 20 hours. After cooling to roomtemperature, the solvent was removed by rotary evaporator and theresulting residue partioned between ethyl acetate and water. The aqueousphase was extracted with two portions of ethyl acetate, the combinedorganic phases washed with brine, dried over magnesium sulfate, filteredand concentrated. The crude product was dissolved in diethyl ether andwashed with two portions of saturated NaHCO₃ and one portion of water.The basic washes were combined and acidified to pH 3 with 1N HCl. Theresulting solid was filtered, washed with copious water and air driedfor 3 hours to give the title compound (1.9 g) as a white solid, m.p.41.5°-43.9° C. (DSC). The structure was supported by NMR, infraredspectroscopy, elemental analysis and mass spectroscopy.

Analysis for C₁₃ H₂₆ O₃ ₀.15 H2O (MW 230.4): Calcd.: C, 67.00; H, 11.37.

Found: C, 66.97; H, 11.18.

EXAMPLE 8 ##STR14## Methyl 12-Methoxydodecanoate

Tetramethylammonium hydroxide pentahydrate (1.7 g, 9.4 mmol) was addedto a solution of the title product of Example 1 (2.0 g, 8.7 mmol) in 45mL of anhydrous acetonitrile. After stirring for 4 hours at roomtemperature, methyl iodide (0.6 mL, 9.6 mmol) was added and theresulting milky solution stirred at room temperature. The solvent wasremoved by rotary evaporator and partioned between diethyl ether andwater. The organic phase was washed with brine, dried over magnesiumsulfate, filtered and concentrated to give the title compound (2.1 g) asa pale yellow liquid. The structure was supported by NMR, infraredspectroscopy, elemental analysis and mass spectroscopy.

Analysis for C₁₄ H₂₈ O₃ (MW 244.4): Calcd.: C, 68.81; H, 11.55.

Found: C, 68.83; H, 11.65.

EXAMPLE 9 ##STR15## Ethyl 12-Methoxydodecanoate

The title compound was prepared by the method of Example 8 using ethyliodide (0.8 mL, 10 mmol) instead of methyl iodide. Concentrationafforded the title compound (2.2 g) as a pale yellow oil. The structurewas supported by NMR, infrared spectroscopy, elemental analysis, andmass spectroscopy.

Analysis for C₁₅ H₃₀ O₃ (MW 258.4): Calcd.: C, 69.72; H, 11.70.

Found: C, 69.74; H, 12.01.

EXAMPLE 10 ##STR16## 4- (7-Methoxyheptyl)oxy!-N-(phenylmethyl)butamide

Oxalyl chloride is added dropwise to a solution of the title product ofExample 5 in anhydrous toluene. After stirring at room temperature, thesolvent is removed on a rotary evaporator, the residue is dissolved inanhydrous toluene and concentrated giving 4-(7-methoxyheptyl)oxy!butanoyl chloride. To a solution of excessbenzylamine in methylene chloride at 0° C. is added dropwise 4-(7-methoxyheptyl)oxy!-butanoyl chloride. After stirring at roomtemperature, the reaction mixture is washed successively with 1N HCl,water, saturated NaHCO₃, water and brine, and is dried over magnesiumsulfate, filtered and concentrated, thereby giving the title compound.The title compound is structurally analogous to theN-(phenylmethyl)alkylamide compounds prepared in Examples 14 and 20,hereinafter, and can be used in place thereof with substantially similarantiviral results.

EXAMPLE 11 ##STR17## 12-Methoxy-1-dodecanoyl Chloride

Oxalyl chloride (16.0 g, 70 mmol) was added dropwise to a solution of12-methoxydodecanoic acid (9.8 g, 77 mmol) in 300 mL of anhydroustoluene. After stirring at room temperature for 16 hours the solvent wasremoved on a rotary evaporator. The residue was taken up in anhydroustoluene and concentrated to give the title compound (17.4 g) as a yellowliquid. The structure was verified by infrared spectroscopy (1796 cm⁻¹)and NMR.

EXAMPLE 12 ##STR18## 12-Methoxydodecanamide

To the title product from Example 11 (1.1 g, 4.3 mmol) in 70 mL ofanhydrous tetrahydrofuran was added 20 mL of freshly distilled liquidammonia in a Parr shaker which was sealed and shaken at room temperaturefor 16 hours. After filtering and concentration, the crude residue wasdissolved in anhydrous methanol and passed through a basic ion exchangeresin and eluted with anhydrous methanol. Concentration afforded thetitle compound (780 mg) as a white solid, m.p. 83.9°-85.6° C. (DSC). Thestructure-was supported by NMR, infrared spectroscopy, elementalanalysis, and mass spectroscopy.

Analysis for C₁₃ H₂₇ NO₂ (MW 229.4): Calcd.: C, 68.08; H, 11.86; N,6.11.

Found: C, 68.40; H, 12.20; N, 5.84.

EXAMPLE 13 ##STR19## 12-Methoxydodecanethioamide

To the title product from Example 12 (1.0 g, 5 mmol) in 70 mL ofanhydrous tetrahydrofuran was added2,4-bis(4-methoxyphenyl)-1,3-dithia-2,4-diphosphetane-2,4-disulfideLawesson's Reagent! (1.0 g, 2 mmol). After stirring at room temperaturefor 1 day, the solvent was removed by rotary evaporator and theresulting residue was purified by chromatography on silica gel using30-70 ethyl acetate-hexane as eluant to give the title compound (625 mg)as a white solid, m.p. 86.8°-89.2° C. (DSC). The structure was supportedby NMR, infrared spectroscopy, elemental analysis, and massspectroscopy.

Analysis for C₁₃ H₂₇ NOS (MW 245.4): Calcd.: C, 63.62; H, 11.09; N,5.71; S, 13.06.

Found: C, 63.59; H, 11.23; N, 5.50; S, 13.03.

EXAMPLE 14 ##STR20## 12-Methoxy-N-(phenylmethyl)dodecanamide

To a solution of benzylamine (486 mg, 4.5 mmol) in 20 mL of methylenechloride at 0° C. was added dropwise diisopropylethylamine (0.45 ml, 5mmol) followed by the title product of example 11 (1.0 g, 4 mmol). Afterstirring at room temperature for 6 days, the reaction mixture was washedsuccessively with 1N HCl, water, saturated NaHCO₃, water and brine,dried over magnesium sulfate, filtered and concentrated. The residue wasdissolved in anhydrous methanol and passed through a basic ion exchangeresin and eluted with anhydrous methanol. Concentration afforded thetitle compound (895 mg) as a white solid, m.p. 77.7°-79.4° C. (DSC). Thestructure was supported by NMR, infrared spectroscopy, elementalanalysis, and mass spectroscopy.

Analysis for C₂₀ H₃₃ NO₂ (MW 319.5): Calcd.: C, 75.19; H, 10.41; N,4.38.

Found: C, 74.87; H, 10.50; N, 4.32.

EXAMPLE 15 ##STR21## N,N-Diethyl-12-methoxydodecanamide

The title compound was prepared by the method of Example 14 usingdiethylamine (331 mg, 4.5 mmol) instead of benzylamine. The residue wasdissolved in anhydrous methanol and passed through a basic ion exchangeresin and eluted with anhydrous methanol. Concentration afforded thetitle compound (826 mg) as a pale yellow liquid. The structure wassupported by NMR, infrared spectroscopy, elemental analysis, and massspectroscopy.

Analysis for C₂₀ H₃₃ NO₂ (MW 319.5): Calcd.: C, 75.19; H, 10.41; N,4.38.

Found: C, 74.87; H, 10.50; N, 4.32.

EXAMPLE 16 ##STR22## 12-Methoxy-N-(2-phenylethyl) dodecanamide

The title compound was prepared by the method of Example 14 using2-phenylethylamine (534 mg, 4.4 mmol) instead of benzylamine.Chromatography of the crude residue on silica gel using 25-75 ethylacetate-hexane as eluant gave the title compound (274 mg) as a whitepowder, m.p. 70.0°-72.5° C. (DSC). The structure was supported by NMR,infrared spectroscopy, elemental analysis, and mass spectroscopy.

Analysis for C₂₁ H₃₅ NO₂ (MW 333.5): Calcd.: C, 75.63; H, 10.58; N,4.20.

Found: C, 75,58; H, 10.72; N, 4.13.

EXAMPLE 17 ##STR23## Ethyl 3- (12-Methoxy-1-oxododecyl)amino!-benzoate

The title compound was prepared by the method of Example 14 using ethyl3-aminobenzoate (1.4 g, 8.8 mmol) instead of benzylamine. Chromatographyof the crude residue on silica gel using 25-75 ethyl acetate-hexane aseluant gave the title compound (1.5 g) as a white powder, m.p.78.5°-81.5° C. (DSC). The structure was supported by NMR, infraredspectroscopy, elemental analysis, and mass spectroscopy.

Analysis for C₂₂ H₃₅ NO₄ (MW 377.5): Calcd.: C, 69.99; H, 9.34; N, 3.71

Found: C, 70.00; H, 9.40; N, 3.67.

EXAMPLE 18 ##STR24## 3- (12-Methoxy-1-oxododecyl)amino!benzoic acid

To a solution of the title product of Example 17 (1.2 g, 3.1 mmol) in 60mL of absolute ethanol was added dropwise an aqueous solution of lithiumhydroxide (7 mL, 2M). After stirring at room temperature for 16 hours,the solvent was removed by rotary evaporator and the resulting residuepartioned between diethyl ether and water. The organic phase was washedwith brine and the aqueous washes combined. The pH of the combinedaqueous washes was adjusted to 2 with 0.5N KHSO₄ and extracted withdiethyl ether followed by methylene chloride. The organic extracts werecombined and concentrated. The crude product was suspended in saturatedNaHCO₃, filtered to remove insoluble materials and acidified with 6NHCl. The resulting solid was filtered, washed with copious water and airdried for 5 hours to give the title compound (371 mg) as a white solid,m.p. 168.6°-171.4° C. (DSC). The structure was supported by NMR,infrared spectroscopy, elemental analysis, and mass spectroscopy.

Analysis for C₂₀ H₃₁ NO₄ 0.4 H₂ O (MW 349.5): Calcd.: C, 67.35; H, 8.99;N, 3.93

Found: C, 67.19; H, 8.95; N, 3.77.

EXAMPLE 19 ##STR25## 3-(Decyloxy)-N,N-diethylpropanamide

To a solution of diethylamine (0.1 mL, 0.97 mmol) in 4.4 mL of methylenechloride was added dropwise diisopropylethylamine (0.2 mL, 1.2 mmol),the title product of Example 7 (205 mg, 0.89 mmol) and1-(3-dimethyl-aminopropyl)-3-ethylcarbodiimide hydrochloride (200 mg,1.0 mmol). After stirring at room temperature, the reaction was dilutedwith methylene chloride and washed successively with water, 1N HCl,water, saturated aqueous NaHCO₃, water and brine, dried over magnesiumsulfate and concentrated. Chromatography of the crude residue on silicagel using 30-70 ethyl acetate-heptane as eluant gave the title compound(96 mg) as a yellow liquid. The structure was supported by NMR, infraredspectroscopy, elemental analysis, and mass spectroscopy.

Analysis for C₁₇ H₃₅ NO₂ (MW 285.5): Calcd.: C, 71.53; H, 12.36; N,4.91.

Found: C, 71.76; H, 12.78; N, 4.81.

EXAMPLE 20 ##STR26## 3-(Decyloxy-N-(phenylmethyl)propanamide

The title compound was prepared by the method of Example 19 usingbenzylamine (103 mg, 0.96 mmol) instead of diethylamine. Radialchromatography of the crude residue on silica gel using 20-80 ethylacetate-heptane as eluant gave the title compound (39 mg) as a whitesolid, m.p. 65.2°-67.7° C. (DSC). The structure was supported by NMR,infrared spectroscopy, elemental analysis, and mass spectroscopy.

Analysis for C₂₀ H₃₃ NO₂ (MW 319.5): Calcd.: C, 75.19; H, 10.41; N,4.38.

Found: C, 75.14; H, 10.42; N, 4.27.

EXAMPLE 21 ##STR27## N-(12-Methoxy-1-oxododecyl)-glycine, Ethyl ester

The title compound was prepared by the method of Example 14 usingglycine ethyl ester hydrochloride (1.2 g, 9.0 mmol) instead ofbenzylamine and triethylamine (2.4 mL, 17 mmol) instead ofdiisopropylethylamine. Concentration afforded the title compound (2.4 g)as a white solid, m.p. 73.9°-76.7° C. (DSC). The structure was supportedby NMR, infrared spectroscopy, elemental analysis and mass spectroscopy.

Analysis for C₁₇ H₃₃ NO₄ (MW 315.4): Calcd.: C, 64.73; H, 10.54; N,4.44.

Found: C, 64.51; H, 10.74; N, 4.43.

EXAMPLE 22 ##STR28##N-(12-Methoxy-1-oxododecyl)-N-(phenylmethyl)-glycine, Ethyl ester

The title compound was prepared by the method of Example 14 usingN-benzylglycine ethyl ester (0.82 mL, 4.4 mmol) instead of benzylamine.Chromatography of the crude residue on silica gel using 20-80 ethylacetate-hexane as eluant gave the title compound (1.1 g) as a paleyellow oil. The structure was supported by NMR, infrared spectroscopy,elemental analysis, and mass spectroscopy.

Analysis for C₂₄ H₃₉ NO₄ (MW 405.6): Calcd.: C, 71.08; H, 9.69; N, 3.45.

Found: C, 71.15; H, 9.90; N, 3.44.

EXAMPLE 23 ##STR29## N-(12-Methoxy-1-oxodecyl)-glycine,1,1-Dimethylethyl ester

The title compound was prepared by the method of Example 14 usingglycine 1,1-dimethylethyl ester hydrochloride (2.0 g, 12 mmol) insteadof benzylamine. Chromatography of the crude residue on silica gel using25-75 ethyl acetate-hexane as eluant gave the title compound (2.3 g) asa white powder, m.p. 38.7°-40.0° C. (DSC). The structure was supportedby NMR, infrared spectroscopy, elemental analysis, and massspectroscopy.

Analysis for C₁₉ H₃₇ NO₄ (MW 343.5): Calcd.: C, 66.44; H, 10.86; N, 4.08.

Found: C, 66.38; H, 11.10; N, 4.03.

EXAMPLE 24 ##STR30## N- N-(12-Methoxy-1-oxododecyl)glycyl!glycine, Ethylester

The title compound was prepared by the method of Example 14 usingglycylglycine ethyl ester hydrochloride salt (356 mg, 2.2 mmol) insteadof benzylamine. Chromatography of the crude residue on silica gel using5-95-0.5 methanol-methylene chloride-ammonium hydroxide as eluant gavethe title compound (500 mg) as a white powder, m.p. 117.9°-121.3° C.(DSC). The structure was supported by NMR, infrared spectroscopy,elemental analysis, and mass spectroscopy.

Analysis for C₁₉ H₃₆ N₂ O₅ (MW 372.5): Calcd.: C, 61.26; H, 9.74; N,7.52.

Found: C, 61.49; H, 9.75; N, 7.40.

EXAMPLE 25 ##STR31##N-(2-Ethoxy-2-oxyethyl)-N-(12-methoxy-1-oxododecyl)glycine, Ethyl ester

The title compound was prepared by the method of Example 14 usingN-(2-ethoxy-2-oxoethyl)glycine ethyl ester (420 mg, 2.2 mmol) instead ofbenzylamine. Chromatography of the crude residue on silica gel using50-50 ethyl acetate-heptane as eluant gave the title compound (694 mg)as a water-white liquid. The structure was supported by NMR, infraredspectroscopy, elemental analysis, and mass spectroscopy.

Analysis for C₂₁ H₃₉ NO₆ (MW 401.5): Calcd.: C, 62.82; H, 9.79; N, 3.49.

Found: C, 62.82; H, 9.97; N, 3.43.

EXAMPLE 26 ##STR32## N-(12-Methoxy-1-oxododecyl)-N-methylglycine, Ethylester

The title compound was prepared by the method of Example 14 usingN-methylglycine ethyl ester hydrochloride (339 mg, 2.2 mmol) instead ofbenzylamine. Chromatography of the crude residue on silica gel using50-50 ethyl acetate-heptane as eluant gave the title compound (580 mg)as a white powder, m.p. 44.1°-47.3° C. (DSC). The structure wassupported by NMR, infrared spectroscopy, elemental analysis, and massspectroscopy.

Analysis for C₁₈ H₃₅ NO₄ (MW 329.5): Calcd.: C, 65.62; H, 10.71; N,4.25.

Found: C, 65.84; H, 10.67; N, 4.21.

EXAMPLE 27 ##STR33## N-phenylglycine, Ethyl ester

To a solution of aniline (9.7 g, 104 mmol) and ethyl bromoacetate (16.3g, 98 mmol) in 150 mL of absolute ethanol was added solid sodium acetate(8.1 g, 99 mmol) in portions. After stirring at room temperature, thesolvent was removed by rotary evaporator and the residue suspended indiethyl ether, filtered through Celite and concentrated. Chromatographyof the crude residue on silica gel using 20-80 ethyl acetate-hexane aseluant gave the title compound (580 mg) as a light brown solid. Thestructure was supported by NMR, infrared spectroscopy, elementalanalysis, and mass spectroscopy.

Analysis for C₁₀ H₁₃ NO₂ (MW 179.2): Calcd.: C, 67.02; H, 7.31; N, 7.82.

Found: C, 66.91; H, 7.41; N, 7.79.

EXAMPLE 28 ##STR34## N-(12-Methoxy-1-oxododecyl)-N,phenylglycine, Ethylester

The title compound was prepared by the method of Example 14 using theproduct of Example 27 (397 mg, 2.2 mmol) instead of benzylamine.Chromatography of the crude residue on silica gel using 25-75 ethylacetate-hexane as eluant gave the title compound (673 mg) as a beigepowder, m.p. 56.8°-59.3° C. (DSC). The structure was supported by NMR,infrared spectroscopy, elemental analysis, and mass spectroscopy.

Analysis for C₂₃ H₃₇ NO₄ (MW 391.6): Calcd.: C, 70.55; H, 9.52; N, 3.58.

Found: C, 70.38; H, 9.28; N, 3.57.

EXAMPLE 29 ##STR35## N- 3-(Decyloxy)-1-oxopropyl!glycine, Ethyl ester

The title compound was prepared by the method of Example 19 usingglycine ethyl ester hydrochloride (131 mg, 0.94 mmol) instead ofdiethylamine. Chromatography of the crude residue on silica gel using50-50-0.5 ethyl acetate-heptane-ammonium hydroxide as eluant gave thetitle compound (185 mg) as a white solid, m.p. 55.0°-56.5° C. (DSC). Thestructure was supported by NMR, infrared spectroscopy, elementalanalysis, and mass spectroscopy.

Analysis for C₁₇ H₃₃ NO₄ (MW 315.4): Calcd.: C, 64.73; H, 10.54; N,4.44.

Found: C, 64.75; H, 10.61; N, 4.38.

EXAMPLE 30 ##STR36## N-(12-Methoxy-1-oxododecyl)-β-alanine, Ethyl ester

The title compound was prepared by the method of Example 14 usingβ-alanine ethyl ester hydrochloride (248 mg, 1.6 mmol) instead ofbenzylamine. Chromatography of the crude residue on silica gel using75-25 ethyl acetate-heptane as eluant gave the title compound (330 mg)as a white solid, m.p. 58.4°-60.3° C. (DSC). The structure was supportedby NMR, infrared spectroscopy, elemental analysis, and massspectroscopy.

Analysis for C₁₈ H₃₅ NO₄ (MW 329.5): Calcd.: C, 65.62; H, 10.71; N,4.25.

Found: C, 65.64; H, 10.90; N, 4.22.

EXAMPLE 31 ##STR37## N-(12-Methoxy-1-oxododecyl)-L-alanine, Ethyl ester

The title compound was prepared by the method of Example 14 usingL-alanine ethyl ester hydrochloride (690 mg, 4.5 mmol) instead ofbenzylamine. Chromatography of the crude residue on silica gel using30-70 ethyl acetate-heptane as eluant gave the title compound (310 mg)as a white powder, m.p. 54.4°-56.5° C. (DSC). The structure wassupported by NMR, infrared spectroscopy, optical rotation ( α!₃₆₅ ²⁵+24.4°, CHCl₃), elemental analysis, and mass spectroscopy.

Analysis for C₁₈ H₃₅ NO₄ (MW 329.5): Calcd.: C, 65.62; H, 10.71; N,4.25.

Found: C, 65.84; H, 10.74; N, 4.13.

EXAMPLE 32 ##STR38## N-(t-Butyloxycarbonyl)-D-alanine, Ethyl ester

The title compound was prepared by the method of Example 8 using ethyliodide (2.4 mL, 30 mmol) instead of methyl iodide and BOC-D-Ala--OH (5.0g, 26.4 mmol) instead of the product of Example 1. Concentrationafforded the title compound (2.8 g) as a pale yellow oil and thestructure verified by NMR.

EXAMPLE 33 ##STR39## D-Alanine Ethyl ester Trifluoroacetate

The title product of Example 32 (2.8 g, 13 mmol) was dissolved in 50%aqueous trifluoroacetic acid and stirred at room temperature and thesolvent removed by rotary evaporator after 1 hour. The residue was takenup with anhydrous toluene and the resulting paste was taken up inabsolute ethanol and concentrated to give the trifluoroacetate salt ofthe title compound (3.2 g) as a brown viscous liquid and the structureverified by NMR.

EXAMPLE 34 ##STR40## N-(12-Methoxy-1-oxododecyl)-D-alanine, Ethyl ester

The title compound was prepared by the method of Example 14 using thetitle product of Example 33 (2.8 g, 12 mmol) instead of benzylamine andtriethylamine (3.4 mL, 24 mmol) instead of diisopropylethylamine.Chromatography of the crude residue on silica gel using 25-75 ethylacetate-hexane as eluant followed by a second chromatography on silicagel using 40-60 ethyl acetate-hexane as eluant gave the title compound(1.6 g) as a white powder, m.p. 53.5°-56.1° C. (DSC). The structure wassupported by NMR, infrared spectroscopy, optical rotation ( α!₃₆₅ ²⁵-22.6°, CHCl₃), elemental analysis, and mass spectroscopy.

Analysis for C₁₈ H₃₅ NO₄ (MW 329.5): Calcd.: C, 65.62; H, 10.71; N,4.25.

Found: C, 66.01; H, 10.64; N, 4.22.

EXAMPLE 35 ##STR41## Ethyl 3-amino-2-methylpropanonate Hydrochloride

To a suspension of 3-aminoisobutyric acid (5.0 g, 48 mmol) in 180 mL ofanhydrous ethanol was added acetylchloride (8.0 mL, 112 mmol) all atonce and the resulting homogeneous solution reluxed for 24 hours. Aftercooling to room temperature, the solvent was removed by rotaryevaporator, the residue was taken up in absolute ethanol andconcentrated to give the hydrochloride salt of title compound (8.7 g) asa yellow liquid and the structure verified by NMR.

EXAMPLE 36 ##STR42## Ethyl 2-(12-methoxy-1-oxododecyl)amino!-2-methyl!propanoate

The title compound was prepared by the method of Example 14 using thetitle product of Example 35 (497 mg, 3 mmol) instead of benzylamine.Chromatography of the crude residue on silica gel using 50-50-0.5 ethylacetate-heptane-ammonium hydroxide as eluant gave the title compound(889 mg) as a white powder, m.p. 53.1°-56.2° C. (DSC). The structure wassupported by NMR, infrared spectroscopy, elemental analysis, and massspectroscopy.

Analysis for C₁₉ H₃₇ NO₄ (MW 343.5): Calcd.: C, 66.44; H, 10.86; N,4.08.

Found: C, 66.12; H, 10.57; N, 4.12.

EXAMPLE 37 ##STR43## EthylN-(t-Butyloxycarbonyl)-3-amino-2R-methylpropanoate

The title compound was prepared by the method of Example 8 using ethyliodide (0.5 mL, 6 mmol) instead of methyl iodide andBOC-3-amino-2S-methyl-propanoic acid (1.0 g, 5 mmol; European PatentAppln. 327,523, published Nov. 7, 1990, Example 4) instead of the titleproduct of Example 1. Concentration afforded the title compound (1.1 g)as a pale yellow oil and the structure verified by NMR.

Analysis for C₁₁ H₂₁ NO₄ (MW 231.3): Calcd.: C, 57.12; H, 9.15; N, 6.06.

Found: C, 56.78; H, 9.18; N, 5.86.

EXAMPLE 38 ##STR44## Ethyl 3-amino-2R-methylpropanoate Trifluoroacete

The title compound was prepared by the method of Example 33 using thetitle product of Example 37 (2.8 g, 13 mmol) instead of the titleproduct of Example 32. Concentration afforded the trifluoroacetate saltof the title compound (1.1 g) as a pale brown liquid and the structureverified by NMR.

EXAMPLE 39 ##STR45## Ethyl 3-(12-methoxy-1-oxododecyl)amino!-2R-methyl!propanoate

The title compound was prepared by the method of Example 14 using thetitle product of Example 38 (1.1 g, 4.6 mmol) instead of benzylamine.Chromatography of the crude residue on silica gel using 50-50-0.5 ethylacetate-heptane-ammonium hydroxide as eluant gave the title compound(714 mg) as a white powder, m.p. 56.8°-59.5° C. The structure wassupported by NMR, infrared spectroscopy, optical rotation ( α!₃₆₅ ²⁵-47.2°, CHCl₃) elemental analysis, and mass spectroscopy.

Analysis for C₁₉ H₃₇ NO₄ (MW 343.5): Calcd.: C, 66.44; H, 10.86; N,4.08.

Found: C, 66.60; H, 10.72; N, 4.06.

EXAMPLE 40 ##STR46## Ethyl N-(p-Methoxybenzyloxycarbonyl)-3-amino-2R(phenylmethyl) propanoate

The title compound was prepared by the method of Example 8 using ethyliodide (0.15 mL, 2 mmol) instead of methyl iodide andN-(p-methoxybenzyloxycarbonyl)-3-amino-2S-(phenylmethyl)propanoic acid(325 mg, 1mmol; European Patent Appln. 327,523, published Nov. 7, 1990,Example 1 and Table 1a) instead of the title product of Example 1.Concentration afforded the title compound (461 mg) as a pale yellowliquid and the structure verified by NMR.

EXAMPLE 41 ##STR47## Ethyl 3-Amino-2R-(phenylmethyl)propanoate

A solution of the title product of Example 40 (260 mg, 0.73 mmol) in 26mL of methanol was hydrogenated in the presence of 4% palladium andcarbon at room temperature under a pressure of 5 pounds per square inchof hydrogen for 2 hours. The reaction was filtered to remove thecatalyst and the solvent removed on a rotary evaporator to give thetitle compound (152 mg) as a beige paste and the structure verified byNMR.

EXAMPLE 42 ##STR48## Ethyl α-(12-Methoxy-1-oxododecyl)amino!methyl!benzenepropanoate

The title compound was prepared by the method of Example 14 using thetitle product of Example 41 (152 mg, 0.75 mmol) instead of benzylamine.Chromatography of the crude residue on silica gel using 20-80 ethylacetate-hexane as eluant gave the title compound (70 mg) as a whitepowder, m.p. 41.0°-44.0° C. (DSC). The structure was supported by NMR,infrared spectroscopy, elemental analysis, and mass spectroscopy.

Analysis for C₂₅ H₄₁ NO₄ (MW 419.6): Calcd.: C, 71.56; H, 9.85; N, 3.34.

Found: C, 71.45; H, 9.84; N, 3.30.

EXAMPLE 43 ##STR49## N-(t-Butyloxycarbonyl)-L-isoleucine Ethyl ester

The title compound was prepared by the method of Example 8 using ethyliodide (0.4 mL, 5 mmol) instead of methyl iodide and BOC-L-Ile--OH-0.5H₂ O (1.0 g, 4 mmol) instead of the title product of Example 1.Concentration afforded the title compound (1.1 g) as a water whiteliquid and the structure verified by NMR.

EXAMPLE 44 ##STR50## L-Isoleucine Ethyl Ester Trifluoroacete

The title compound was prepared by the method of Example 33 using thetitle product of Example 43 (1.1 g, 4 mmol) instead of the title productof Example 32. Concentration afforded the trifluroracetate salt of thetitle compound (1.3 g) as a pale yellow liquid and the structureverified by NMR.

EXAMPLE 45 ##STR51## N-(12-Methoxy-1-oxododecyl)-L-isoleucine, Ethylester

The title compound was prepared by the method of Example 14 using thetitle product of Example 44 (1.1 g, 4 mmol) instead of benzylamine.Chromatography of the crude residue on silica gel using 50-50 ethylacetate-heptane as eluant gave the title compound (875 mg) as a whitepowder, m.p. 36.4°-38.1° C. (DSC). The structure was supported by NMR,infrared spectroscopy, optical rotation ( α!₃₆₅ ²⁵ +81.9°, CHCl₃),elemental analysis, and mass spectroscopy.

Analysis for C₂₁ H₄₁ NO₄ (MW 371.6): Calcd.: C, 67.88; H, 11.12; N,3.77.

Found: C, 67.85; H, 11.25; N, 3.74.

EXAMPLE 46 ##STR52## N-(t-Butyloxycarbonyl)-D-isoleucine, Ethyl ester

The title compound was prepared by the method of Example 8 using ethyliodide (0.4 mL, 5 mmol) instead of methyl iodide and BOC-D-Ile--OH-0.5H₂ O (1.0 g, 4 mmol) instead of the title product of Example 1.Concentration afforded the title compound (1.2 g) as a water whiteliquid and the structure verified by NMR.

EXAMPLE 47 ##STR53## D-Isoleucine Ethyl Ester Trifluoroacete

The title compound was prepared by the method of Example 33 using thetitle product of Example 46 (1.1 g, 4 mmol) instead of the title productof Example 32. Concentration afforded the trifluoroacetate salt of thetitle compound (1.2 g) as a pale brown liquid and the structure verifiedby NMR.

EXAMPLE 48 ##STR54## N-(12-Methoxy-1-oxododecyl)-D-isoleucine, Ethylester

The title compound was prepared by the method of Example 14 using thetitle product of Example 47 (1.1 g, 4 mmol) instead of benzylamine.Chromatography of the crude residue on silica gel using 50-50 ethylacetate-heptane as eluant gave the title compound (905 mg) as a whitepowder, m.p. 35.8°-38.2° C. (DSC). The structure was supported by NMR,infrared spectroscopy, optical rotation ( α!₃₆₅ ²⁵ -77.4°, CHCl₃)elemental analysis, and mass spectroscopy.

Analysis for C₂₁ H₄₁ NO₄ (MW 371.6): Calcd.: C, 67.88; H, 11.12; N,3.77.

Found: C, 67.64; H, 10.88; N, 3.65.

EXAMPLE 49 ##STR55## N-(12-Methoxy-1-oxododecyl)-L-phenylalanine, Ethylester

The title compound was prepared by the method of Example 14 usingL-phenylalanine ethyl ester hydrochloride (2.0 g, 8.8 mmol) instead ofbenzylamine and triethylamine (1.2 mL, 8.6 mmol) instead ofdiisopropylethylamine. Chromatography of the crude residue on silica gelusing 40-60 ethyl acetate-hexane as eluant gave the title compound (1.6g) as a white powder, m.p. 51.0°-53.4° C. The structure was supported byNMR, infrared spectroscopy, optical rotation ( α!₃₆₅ ²⁵ +220.2°, CHCl₃),elemental analysis, and mass spectroscopy.

Analysis for C₂₄ H₃₉ NO₄ (MW 405.6): Calcd.: C, 71.08; H, 9.69; N, 3.45.

Found: C, 71.20; H, 9.72; N, 3.43.

EXAMPLE 50 ##STR56## N-(12-Methoxy-1-oxododecyl)-L-phenylalanine,1,1-Dimethylethyl ester

The title compound was prepared by the method of Example 14 usingL-phenylalanine 1,1-dimethylethyl ester (971 mg, 4.4 mmol) instead ofbenzylamine and triethylamine (0.61 mL, 4.4 mmol) instead ofdiisopropylethylamine. Chromatography of the crude residue on silica gelusing 50-50 ethyl acetate-hexane as eluant gave the title compound (1.1g) as a water white liquid. The structure was supported by NMR, infraredspectroscopy, optical rotation ( α!₃₆₅ ²⁵ +192.8°, CHCl₃), elementalanalysis, and mass spectroscopy.

Analysis for C₂₆ H₄₃ NO₄ (MW 433.6): Calcd.: C, 72.02; H, 10.00; N,3.23.

Found: C, 71.62; H, 10.20; N, 3.13.

EXAMPLE 51 ##STR57## D-Phenylalanine Ethyl ester p-Toluenesulfonate

A mixture of D-phenylalanine (5.0 g, 30 mmol) and p-toluenesulfonic acidmonohydrate (12.7 g, 67 mmol) in 150 mL of anhydrous ethanol wasrefluxed for 24 hours. After cooling to room temperature, the solventwas removed by rotary evaporator, the residue triturated with diethylether, filtered and dried in vacuo over P₂ O₅ to give thep-toluenesulfonate salt of the title compound (9.7 g) as a white solidand the structure verified by NMR.

EXAMPLE 52 ##STR58## N-(12-Methoxy-1-oxododecyl)-D-phenylalanine, Ethylester

The title compound was prepared by the method of Example 14 using thetitle product of Example 51 (3.3 g, 8.9 mmol) instead of benzylamine andtriethylamine (2.5 mL, 18 mmol) instead of diisopropylethylamine.Chromatography of the crude residue on silica gel using 25-75 ethylacetate-hexane as eluant gave the title compound (2.4 g) as a whitesolid, m.p. 51.0°-53.1° C. (DSC). The structure was supported by NMR,infrared spectroscopy, optical rotation ( α!₃₆₅ ²⁵ -221.8°, CHCl₃),elemental analysis, and mass spectroscopy.

Analysis for C₂₄ H₃₉ NO₄ (MW 405.6): Calcd.: C, 71.08; H, 9.69; N, 3.45.

Found: C, 71.08; H, 9.86; N, 3.42.

EXAMPLE 53 ##STR59## D-Phenylalanine 1,1-Dimethylethyl ester

To a solution of D-phenylalanine (5.5 g, 33 mmol) in 430 mL of t-butylacetate was added concentrated perchloric acid (2 mL, 33 mmol). Afterstirring at room temperature, the reaction mixture was filtered and thefilter cake washed with copious diethyl ether. The filter cake wassuspended in diethyl ether and washed with two portions of 5% citricacid. The acid washes were combined, neutralized with solid NaHCO₃ andextracted with two portions of diethyl ether. The combined organicextracts were washed with brine, dried with magnesium sulfate andconcentrated to give the title compound (404 mg) as a pale yellow liquidand the structure verified by NMR.

EXAMPLE 54 ##STR60## N-(12-Methoxy-1-oxododecyl)-D-phenylalanine,1,1-Dimethylethyl ester

The title compound was prepared by the method of Example 14 using thetitle product of Example 53 (292 mg, 1.3 mmol) instead of benzylamineand triethylamine (0.2 mL, 1.4 mmol) instead of diisopropylethylamine.Chromatography of the crude residue on silica gel using 25-75 ethylacetate-hexane as eluant gave the title compound (496 mg) as a paleyellow liquid. The structure was supported by NMR, infraredspectroscopy, optical rotation ( α!₃₆₅ ²⁵ -188.2°, CHCl₃), elementalanalysis, and mass spectroscopy.

Analysis for C₂₆ H₄₃ NO₄ (MW 433.6): Calcd.: C, 72.02; H, 10.00; N,3.23.

Found: C, 71.20; H, 9.96; N, 3.13.

EXAMPLE 55 ##STR61## N-(3-(Decycloxy)-1-oxopropyl!-L-phenylalanine,Ethyl ester

The title compound was prepared by the method of Example 19 using theL-phenylalanine ethyl ester hydrochloride (214 mg, 0.93 mmol) instead ofdiethylamine. Radial chromatography of the crude residue on silica gelusing 20-80 ethyl acetate-hexane as eluant gave the title compound (329mg) as a white solid, m.p. 50.3°-52.4° C. (DSC). The structure wassupported by NMR, infrared spectroscopy, optical rotation ( α!₃₆₅ ²⁵+180.6°, CHCl₃), elemental analysis, and mass spectroscopy.

Analysis for C₂₄ H₃₉ NO₄ (MW 405.6): Calcd.: C, 71.08; H, 9.69; N, 3.45.

Found: C, 70.88; H, 9.81; N, 3.38.

EXAMPLE 56 ##STR62## N-(3-(Decyloxy)-1-oxopropyl!-D-phenylalanine, Ethylester

The title compound was prepared by the method of Example 19 using thetitle product of Example 51 (348 mg, 0.95 mmol) instead of diethylamine.Radial chromatography of the crude residue on silica gel using 20-80ethyl acetate-hexane as eluant gave the title compound (275 mg) as awhite solid, m.p. 51.4°-54.7° C. (DSC). The structure was supported byNMR, infrared spectroscopy, elemental analysis, optical rotation ( α!₃₆₅²⁵ -178.3°, CHCl₃)and mass spectroscopy

Analysis for C₂₄ H₃₉ NO₄ (MW 405.6): Calcd.: C, 71.08; H, 9.69;N, 3.45.

Found: C, 70.96; H, 9.61; N, 3.41.

EXAMPLE 57 ##STR63## N-(t-Butyloxycarbonyl)-L-glutamic acid, 1-Ethyl5-(Phenylmethyl) ester

The title compound was prepared by the method of Example 8 using ethyliodide (0.3 mL, 3.8 mmol) instead of methyl iodide andBOC-L-Glu(O-benzyl)--OH (1.0 g, 3.1 mmol) instead of the title productof Example 1. Concentration afforded the title compound (1.1 g) as awhite wax and the structure verified by NMR.

EXAMPLE 58 ##STR64## L-glutamic acid, 1-Ethyl 5-(Phenylmethyl) esterTrifluoroacetate

The title compound was prepared by the method of Example 33 using thetitle product of Example 57 (1.1 g, 4 mmol) instead of the title productof Example 32. Concentration afforded the trifluoroacetate salt of thetitle compound (1.2 g) as a pale brown liquid and the structure verifiedby NMR.

EXAMPLE 59 ##STR65## N-(12-methoxy-1-oxododecyl)-L glutamic acid,1-Ethyl 5-(Phenylmethyl) ester

The title compound was prepared by the method of Example 14 using thetitle product of Example 58 (1.1 g, 2.9 mmol) instead of benzylamine.Chromatography of the crude residue on silica gel using 50-50 ethylacetate-heptane as eluant gave the title compound (942 mg) as a paleyellow solid, m.p. 42.7°-45.0° C. (DSC). The structure was supported byNMR, infrared spectroscopy, optical rotation ( α!₃₆₅ ²⁵ +57.7°, CHCl₃),elemental analysis, and mass spectroscopy.

Analysis for C₂₇ H₄₃ NO₆ (MW 477.6): Calcd.: C, 67.90; H, 9.07; N, 2.93.

Found: C, 66.68; H, 8.99; N, 2.96.

EXAMPLE 60 ##STR66## N-(t-Butyloxycarbonyl)-D-glutamic acid, 1-Ethyl5-(phenylmethyl) ester

The title compound was prepared by the method of Example 8 using ethyliodide (0.3 mL, 3.8 mmol) instead of methyl iodide andBOC-D-Glu(O-benzyl)--OH (1.0 g, 3.0 mmol) instead of the title productof Example 1. Concentration afforded the title compound (1.1 g) as ayellow liquid and the structure verified by NMR.

EXAMPLE 61 ##STR67## D-glutamic acid, 1-Ethyl 5-(Phenylmethyl) esterTrifluoroacetate

The title compound was prepared by the method of Example 33 using thetitle product of Example 60 (1.1 g, 3 mmol) instead of the title productof Example 32. Concentration afforded the trifluoroacetic salt of thetitle compound (1.1 g) as a pale brown liquid and the structure verifiedby NMR.

EXAMPLE 62 ##STR68## N-(12-methoxy-1-oxododecyl)-D-glutamic acid,1-Ethyl 5-(Phenylmethyl) ester

The title compound was prepared by the method of Example 14 using thetitle product of Example 61 (1.1 g, 2.9 mmol) instead of benzylamine.Chromatography of the crude residue on silica gel using 50-50 ethylacetate-heptane as eluant gave the title compound (839 mg) as a paleyellow solid, m.p. 38.4°-42.1° C. (DSC). The structure was supported byNMR, infrared spectroscopy, optical rotation ( α!₃₆₅ ²⁵ -54.0°, CHCl₃),elemental analysis, and mass spectroscopy.

Analysis for C₂₇ H₄₃ NO₆ (MW 477.6): Calcd.: C, 67.90; H, 9.07; N, 2.93.

Found: C, 67.43; H, 9.27; N, 2.97.

EXAMPLE 63 ##STR69## N6- (2-Chlorophenyl)methoxy!carbonyl!-N2-t-butyloxycarbonyl!-L-lysine, Ethyl ester

The title compound was prepared by the method of Example 8 using ethyliodide (0.24 mL, 3.0 mmol) instead of methyl iodide and BOC-L-Lys((2-chlorophenyl)methoxy!carbonyl)--OH (1.0 g, 2.5 mmol) instead of thetitle product of Example 1. Concentration afforded the title compound(1.1 g) as a yellow liquid and the structure verified by NMR.

EXAMPLE 64 ##STR70## N6- (2-Chlorophenyl)methoxy!carbonyl!-L-lysine,Ethyl ester Trifluoroacetate

The title compound was prepared by the method of Example 33 using thetitle product of Example 63 (1.1 g, 2.5 mmol) instead of the titleproduct of Example 32. Concentration afforded the trifluoroacetate saltof the title compound (1.2 g) as a pale brown liquid and the structureverified by NMR.

EXAMPLE 65 ##STR71## N6-(2-Chlorophenyl)methoxy!carbonyl!-N2-(12-methoxy-1 oxododecyl)-L-lysine,ethyl ester

The title compound was prepared by the method of Example 14 using thetitle product of Example 64 (1.2 g, 2.6 mmol) instead of benzylamine.Chromatography of the crude residue on silica gel using 50-50 ethylacetate-heptane as eluant gave the title compound (642 mg) as a paleyellow solid, m.p. 62.0°-64.2° C. (DSC). The structure was supported byNMR, infrared spectroscopy, optical rotation ( α!₃₆₅ ²⁵ +39.2°, CHCl₃),elemental analysis, and mass spectroscopy.

Analysis for C₂₉ H₄₇ N₂ O₆ Cl (MW 555.2): Calcd.: C, 62.74; H, 8.53; N,5.05; Cl, 6.39.

Found: C, 62.74; H, 8.44; N, 5.07; C, 6.41.

EXAMPLE 66 ##STR72## N₆ - (2-Chlorophenyl)methoxy!carbonyl!N2-t-butyloxycarbonyl!-D-lysine, Ethyl ester

The title compound was prepared by the method of Example 8 using ethyliodide (0.18 mL, 2.2 mmol) instead of methyl iodide and BOC-D-Lys((2-chlorophenyl)methoxy!carbonyl)--OH t-butylamine (1.0 g, 1.8 mmol)instead of the title product of Example 1. Concentration afforded thetitle compound (717 mg) as a yellow oil and the structure verified byNMR.

EXAMPLE 67 ##STR73## N6- (2-Chlorophenyl)methoxy!carbonyl-D-lysine,Ethyl ester Trifluoroacetate

The title compound was prepared by the method of Example 33 using thetitle product of Example 66 (717 mg, 1.6 mmol) instead of the titleproduct of Example 32. Concentration afforded the trifluoroacetate saltof the title compound (765 mg) as a pale brown liquid and the structureverified by NMR.

EXAMPLE 68 ##STR74## N₆ -(2-Chlorophenyl)methoxy!carbonyl!-N2-(12-methoxy-1-oxododecyl)-D-lysine,Ethyl ester

The title compound was prepared by the method of Example 14 using thetitle product of Example 68 (740 mg, 1.7 mmol) instead of benzylamine.Chromatography of the crude residue on silica gel using 50-50 ethylacetate-heptane as eluant gave the title compound (596 mg) as a whitesolid, m.p. 62.4°-64.2° C. (DSC). The structure was supported by NMR,infrared spectroscopy, optical rotation ( α!₃₆₅ ²⁵ -41.8°, CHCl₃),elemental analysis, and mass spectroscopy.

Analysis for C₂₉ H₄₇ N₂ O₆ Cl (MW 555.2): Calcd.: C, 62.74; H, 8.53; N,5.05; Cl, 6.39.

Found: C, 62.60; H, 8.52; N, 5.00; Cl, 6.39.

EXAMPLE 69 ##STR75## N-(t-Butyloxycarbonyl)-L-tryptophan, Ethyl ester

The title compound was prepared by the method of Example 8 using ethyliodide (0.35 mL, 4.4 mmol) instead of methyl iodide and BOC-L-Trp--OH(1.1 g, 3.6 mmol) instead of the title product of Example 1.Concentration afforded the title compound (1.2 g) as a yellow oil andthe structure verified by NMR.

EXAMPLE 70 ##STR76## L-Tryptophan Ethyl ester Trifluoroacetate

The title compound was prepared by the method of Example 33 using thetitle product of Example 69 (1.2 g, 3.5 mmol) instead of the titleproduct of Example 32. Concentration afforded the trifluoroacetate saltof the title compound (1.2 g) as a pale brown liquid and the structureverified by NMR.

EXAMPLE 71 ##STR77## N-(12-Methoxy-1-oxododecyl)-L-tryptophan, Ethylester

The title compound was prepared by the method of Example 14 using thetitle product of Example 70 (1.2 g, 3.5 mmol) instead of benzylamine.Chromatography of the crude residue on silica gel using 50-50 ethylacetate-heptane as eluant gave the title compound (671 mg) as a paleyellow paste. The structure was supported by NMR, infrared spectroscopy,optical rotation ( α!₃₆₅ ²⁵ +1559°, CHCl₃), elemental analysis, and massspectroscopy.

Analysis for C₂₆ H₄₀ N₂ O₄ (MW 444.6): Calcd.: C, 70.24; H, 9.07; N,6.30.

Found: C, 70.08; H, 9.20; N, 6.27.

EXAMPLE 72 ##STR78## N-(t-Butyloxycarbonyl)-D-tryptophan, Ethyl ester

The title compound was prepared by the method of Example 8 using ethyliodide (0.35 mL, 4.4 mmol) instead of methyl iodide and BOC-D-Trp--OH(1.0 g, 3.3 mmol) instead of the title product of Example 1.Concentration afforded the title compound (1.1 g) as a white solid andthe structure verified by NMR.

EXAMPLE 73 ##STR79## D-Tryptophan, Ethyl ester Trifluoroacetate

The title compound was prepared by the method of Example 33 using thetitle product of Example 72 (1.1 g, 3.3 mmol) instead of the titleproduct-of Example 32. Concentration afforded the trifluoroacetate saltof the title compound (1.2 g) as a pale brown liquid and the structureverified by NMR.

EXAMPLE 74 ##STR80## N-(12-Methoxy-1-oxododecyl)-D-tryptophan, Ethylester

The title compound was prepared by the method of Example 14 using thetitle product of Example 73 (1.2 g, 3.5 mmol) instead of benzylamine.Chromatography of the crude residue on silica gel using 50-50 ethylacetate-heptane as eluant gave the title compound (650 mg) as a yellowoil. The structure was supported by NMR, infrared spectroscopy, opticalrotation ( α!₃₆₅ ²⁵ -156.2°, CHCl₃), elemental analysis, and massspectroscopy.

Analysis for C₂₆ H₄₀ N₂ O₄ (MW 444.6): Calcd.: C, 70.24; H, 9.07; N,6.30.

Found: C, 69.24; H, 9.13; N, 6.12.

EXAMPLE 75 ##STR81## N-(t-Butyloxycarbonyl)-O-phenylmethyl)-L-threonine,Ethyl ester

The title compound was prepared by the method of Example 8 using ethyliodide (0.31 mL, 3.9 mmol) instead of methyl iodide andBOC-L-Thr-(O-benzyl)--OH (1.0 g, 3.4 mmol) instead of the title productof Example 1. Concentration afforded the title compound (818 mg) as awater-white liquid and the structure verified by NMR.

EXAMPLE 76 ##STR82## O-(Phenylmethyl)-L-threonine, Ethyl esterTrifluoroacetate

The title compound was prepared by the method of Example 33 using thetitle product of Example 75 (818 mg, 2.4 mmol) instead of the titleproduct of Example 32. Concentration afforded the trifluoroacetate saltof the title compound (821 mg) as a pale brown liquid and the structureverified by NMR.

EXAMPLE 77 ##STR83##N-(12-methoxy-1-oxododecyl)-O-(phenylmethyl)-L-threonine, Ethyl ester

The title compound was prepared by the method of Example 14 using thetitle product of Example 76 (821 mg, 2.3 mmol) instead of benzylamine.Chromatography of the crude residue on silica gel using 50-50 ethylacetate-heptane as eluant gave the title compound (632 mg) as a whitesolid, m.p. 42.9 °-46.9° C. (DSC). The structure was supported by NMR,infrared spectroscopy, optical rotation ( α!₃₆₅ ²⁵ +36.0°, CHCl₃),elemental analysis, and mass spectroscopy.

Analysis for C₂₆ H₄₃ NO₅ (MW 449.6): Calcd.: C, 69.45; H, 9.64; N, 3.12.

Found: C, 69.20; H, 9.52; N, 3.13.

EXAMPLE 78 ##STR84##N-(t-Butyloxycarbonyl)-O-(phenylmethyl)-D-threonine, Ethyl ester

The title compound was prepared by the method of Example 8 using ethyliodide (0.31 mL, 3.9 mmol) instead of methyl iodide andBOC-D-Thr-(O-benzyl)--OH (1.0 g, 3.2 mmol) instead of the title productof Example 1. Concentration afforded the title compound (1.0 g) as ayellow liquid and the structure verified by NMR.

EXAMPLE 79 ##STR85## O-(Phenylmethyl)-D-threonine, Ethyl esterTrifluoroacetate

The title compound was prepared by the method of Example 33 using thetitle product of Example 78 (1.0 g, 3.0 mmol) instead of the titleproduct-of Example 32. Concentration afforded the trifluoroacetate saltof the title compound (919 mg) as a pale brown liquid and the structureverified by NMR.

EXAMPLE 80 ##STR86##N-(12-methoxy-1-oxododecyl)-O-(phenylmethyl)-D-threonine, Ethyl ester

The title compound was prepared by the method of Example 14 using thetitle product of Example 79 (919 mg, 2.6 mmol) instead of benzylamine.Chromatography of the crude residue on silica gel using 50-50 ethylacetate-heptane as eluant gave the title compound (755 mg) as a whiteflaky solid, m.p. 38.1°-47.0° C. (DSC). The structure was supported byNMR, infrared spectroscopy, optical rotation ( α!₃₆₅ ²⁵ -37.0°, CHCl₃),elemental analysis, and mass spectroscopy.

Analysis for C₂₆ H₄₃ NO₅ (MW 449.6): Calcd.: C, 69.45; H, 9.64; N, 3.12.

Found: C, 69.19; H, 9.59; N, 3.16.

EXAMPLE 81 ##STR87## N-(12-Methoxy-1-oxodecyl)glycine

To the title product of Example 23 (321 mg, 0.93 mmol) in 1 mL ofdioxane was added dropwise a solution of hydrochloric acid in dioxane (1mL, 4M). After stirring at room temperature, the solvent was removed byrotary evaporator and the resulting residue was taken up in anhydroustoluene and concentrated to give the title compound (254 mg) as a whitesolid m.p. 103.1°-104.7° C. (DSC). The structure was supported by NMR,elemental analysis, and mass spectroscopy.

Analysis for C₁₅ H₂₉ NO₄ (MW 287.4): Calcd.: C, 62.69; H, 10.19; N,4.87.

Found: C, 62.37; H, 10.19; N, 4.80.

EXAMPLE 82 ##STR88## N-(12-Methoxy-1-oxododecyl)-L-phenylalanine

The title compound was prepared by the method of Example 81 using thetitle product of Example 50 (301 mg, 0.69 mmol) instead of the titleproduct of Example 23. Chromatography of the crude residue on silica gelusing 50-50-1 ethyl acetate-heptane-acetic acid as eluant gave the titlecompound (172 mg) as a white powder, m.p. 73.3 °-77.3° C. (DSC). Thestructure was supported by NMR, infrared spectroscopy, optical rotation( α!₃₆₅ ²⁵ +226.0°, CHCl₃), and elemental analysis.

Analysis for C₂₂ H₃₅ NO₄ (MW 377.5): Calcd.: C, 69.99; H, 9.34; N, 3.71.

Found: C, 69.83; H, 8.94; N, 3.65.

EXAMPLE 83 ##STR89## N-(12-Methoxy-1-oxododecyl)-D-phenylalanine

The title compound was prepared by the method of Example 81 using thetitle product of Example 54 (135 mg, 0.31 mmol) instead of the titleproduct of Example 23. Chromatography of the crude residue on silica gelusing 50-50-1 ethyl acetate-heptane-acetic acid as eluant gave the titlecompound (83 mg) as a white powder, m.p. 69.3°-72.8° C. The structurewas supported by NMR, infrared spectroscopy, optical rotation ( α!₃₆₅ ²⁵-222.9°, CHCl₃), and elemental analysis.

Analysis for C₂₂ H₃₅ NO₄ (MW 377.5): Calcd.: C, 69.99; H, 9.34; N, 3.71.

Found: C, 69.67; H, 9.35; N, 3.65.

EXAMPLE 84 CH₃ O(CH₂)₁₁ C.tbd.N

12-Methoxydodecanenitrile

To the title compound of Example 12 (5.0 g, 22 mmol) in 30 mL pyridineat 0° C. was added in portions p-toluenesulfonyl chloride (5.1 g, 27mmol). After stirring at room temperature for 3 days, the reactionmixture was filtered, the cake washed with methylene chloride and thefiltrate concentrated. The resulting residue was dissolved in methylenechloride, washed successively with 1N HCl, water, saturated NaHCO₃,water and brine, dried with magnesium sulfate, filtered andconcentrated. Chromatography of the crude product on silica gel using20-80 diethyl ether-hexane as eluant gave the title compound (3.4 g) asa pale yellow liquid. The structure was supported by NMR, infraredspectroscopy, elemental analysis and mass spectroscopy.

Analysis for C₁₃ H₂₅ NO (MW 211.4): Calcd.: C, 73.88; H, 11.92: N, 6.63.

Found: C, 73.57; H, 12.07; N, 6.41.

EXAMPLE 85 ##STR90## 5-(11-Methoxyundecyl)-1H-tetrazole

To the title compound of Example 84 (1.0 g, 4.8 mmol) in 10 mL oftoluene at room temperature was added successively sodium azide (929 mg,14 mmol), lithium chloride (596 mg, 14 mmol) and chlorotributyltin (1.5mL, 5.5 mmol). The heterogeneous mixture was refluxed for two days,diluted with 10 mL toluene and refluxing continued for 24 hours. Aftercooling to room temperature, the reaction mixture was filtered and thecake washed with copious toluene. The resulting white cake was dissolvedin water, acidified to pH 6 with 1N HCl and extracted with threeportions of methylene chloride. The combined organic extracts werewashed with brine, dried with magnesium sulfate and concentrated to givethe title compound (600 mg) as a white powder, m.p. 66.3°-68.3° C.(DSC). The structure was supported by NMR, infrared spectroscopy,elemental analysis and mass spectroscopy.

Analysis for C₁₃ H₂₆ N₄ O (MW 254.4): Calcd.: C, 61.38; H, 10.30; N,22.05.

Found: C, 61.25; H, 10.53; N, 21.83.

EXAMPLE 86 ##STR91## A. 1-Ethyl-5-(11-methoxyundecyl)-1H-tetrazole##STR92## 2-Ethyl-5-(11-methoxyundecyl)-2H-tetrazole

Sodium hydride dispersed in mineral oil (192 mg, 4.8 mmol; washed threetimes with hexane) was treated with the title product of Example 85 (1.1g, 4.2 mmol) in 10 mL of dimethylformamide for 16 hours at roomtemperature followed by the addition of ethyl iodide (0.38 mL, 4.8mmol). After stirring at room temperature for 24 hours, the solvent wasremoved by rotary evaporator and the resulting residue partioned betweenethyl acetate and water and the aqueous phase extracted with ethylacetate. The combined organic phases were washed with water and brine,dried with magnesium sulfate and concentrated. Chromatography of thecrude residue on silica gel using 25-75 ethyl acetate-hexane gave titlecompound B (674 mg) as a pale yellow liquid and title compound A (414mg) as a white powder, m.p. 51.0°-52.8° C. (DSC). Both structures weresupported by NMR, infrared spectroscopy, elemental analysis and massspectroscopy.

Analysis for A: C₁₅ H₃₀ N₄ O (MW 282.4): Calcd.: C, 63.79; H, 10.71; N,19.84.

Found: C, 63.82; H, 10.76; N, 19.75.

Analysis for B: C₁₅ H₃₀ N₄ O (MW 282.4): Calcd.: C, 63.79; H, 10.71; N,19.84.

Found: C, 63.66; H, 10.61; N, 19.74.

EXAMPLE 87 ##STR93## A.5-(11-Methoxyundecyl)-1-(phenylmethyl)-1H-tetrazole ##STR94## B.5-(11-Methoxyundecyl)-2-(phenylmethyl)-2H-tetrazole

The title compounds were prepared by the method of Example 86 usingbenzylbromide (1.1 mL, 9.3 mmol) instead of ethyl iodide. Chromatographyof the crude residue on silica gel using 40-60 ethyl acetate-hexane gavetitle compound B (1.1 g) as a pale yellow liquid and title compound A(1.5 g) as a white powder, m.p. 58.8°-60.8° C. (DSC). Both structureswere supported by NMR, infrared spectroscopy, elemental analysis andmass spectroscopy.

Analysis for A: C₂₀ H₃₂ N₄ O (MW 344.5): Calcd.: C, 69.73; H, 9.36; N,16.26.

Found: C, 69.77; H, 9.69; N, 16.45.

Analysis for B: C₂₀ H₃₂ N₄ O (MW 344.5): Calcd.: C, 69.73; H, 9.36; N,16.26.

Found: C, 70.26; H, 9.64; N, 15.75.

EXAMPLE 88 CH₃ O(CH₂)₁₁ CH₂ OH

12-Methoxydodecanol

The title compound was prepared by the method of Example 3 using thetitle product of Example 1 (3 g, 13 mmol) instead of the title productof Example 2. Chromatography by of the crude residue on silica gel using50-50 ethyl acetate heptane gave the title compound (2.2 g) as a whitepowder, m.p. 32.6°-36.7° C. (DSC). The structure was supported by NMR,infrared spectroscopy, elemental analysis and mass spectroscopy.

Analysis for C₁₃ H₂₈ O₂ (MW 216.4): Calcd.: C, 72.17; H, 13.01.

Found: C, 72.27; H, 13.25.

EXAMPLE 89 ##STR95## 13-Methoxy-2-tridecanone

To the title product of Example 84 (516 mg, 2.4 mmol) in 10 mL ofanhydrous diethyl ether was added dropwise a solution of methylmagnesiumbromide in diethyl ether (1.2 mL, 3.2M) at room temperature. Afterrefluxing for 5 days, the reaction was cooled to room temperature,poured into aqueous 1N HCl and stirred vigorously for 3 days. The layerswere separated and the aqueous phase extracted with one portion each ofdiethyl ether and ethyl acetate. The combined organic extracts werewashed with saturated NaHCO₃, water and brine, dried with magnesiumsulfate and concentrated. Chromatography by of the crude residue onsilica gel using 20-80 ethyl acetate heptane gave the title compound(311 mg) as a yellow-brown liquid. The structure was supported by NMR,infrared spectroscopy, and elemental analysis.

Analysis for C₁₄ H₂₈ O₂ (MW 228.4): Calcd.: C, 73.63; H, 12.36.

Found: C, 73.34; H, 12.23.

EXAMPLE 90

When 11-(ethylthio)undecanoic acid is substituted for an equivalentamount of 12-methoxydodecanoic acid in Example 11 and then the resulting11-(ethylthio)undecanoyl chloride is substituted for an equivalentamount of 12-methoxydodecanoyl chloride in Example 12, the compound11-(ethylthio)undecanamide is prepared and can be used in place of the12-methoxydodecanamide with substantially similar antiviral results.

EXAMPLE 91

When 5-(octylthio)pentanoic acid is substituted for an equivalent amountof 12-methoxydodecanoic acid in Example 11 and then the resulting5-(octylthio)pentanoyl chloride is substituted for an equivalent amountof 12-methoxydodecanoyl chloride in Example 12, the compound5-(octylthio)pentanamide is prepared and can be used in place of the12-methoxydodecanamide with substantially similar antiviral results.

EXAMPLE 92

When 6,12-dithiatetradecanoic acid is substituted for an equivalentamount of 12-methoxydoecanoic acid in Example 11 and then the resulting6,12-dithiatetradecanoyl chloride is substituted for an equivalentamount of the 12-methoxydodecanoyl chloride in Example 12, the compound6,12-dithiatetradecanamide is prepared and can be used in place of the12-methoxy-dodecanamide with substantially similar antiviral results.

EXAMPLE 93

When any of 12-azidodecanoic acid or 12-(tetrazolyl)dodecanoic acid or12-(triazolyl)dodecanoic acid are substituted for an equivalent amountof 12-methoxydodecanoic acid in Example 11 and then the resulting acylchloride products are substituted for an equivalent amount of the12-methoxydodecanoyl chloride of Example 12, the compounds12-azidododecanamide, 12-(tetrazolyl) dodecanamide and12-(triazolyl)dodecanamide, respectively, are prepared and can be usedin place of the 12-methoxydodecanamide with substantially similarantiviral results.

EXAMPLE 94

When any of the acyl chloride products prepared in Examples 90-93 aresubstituted for an equivalent amount of the 12-methoxydodecanoylchloride in Example 14, the resulting11-(ethylthio)-N-(phenylmethyl)undecanamide or5-(octylthio)-N-(phenylmethyl)pentanamide or6,12-dithia-N-(phenylmethyl)tetradecanamide or12-azido-N-(phenylmethyl)dodecanamide or12-(tetrazolyl-N-(phenylmethyl)dodecanamide or12-(triazolyl)-N-(phenylmethyl)dodecanamide, respectively, are preparedand can be used in place of the 12-methoxy-N-(phenylmethyl)dodecanamidewith substantially similar antiviral results.

EXAMPLE 95

When Example 94 is repeated except that the procedure of Example 50 isemployed whereby L-phenylalanine 1,1-dimethylethyl ester andtriethylamine are used as reactants instead of benzylamine anddiisopropylethylamine, respectively, the correspondingN-(L-phenylalanine dimethylethyl ester) amides are prepared instead ofthe N-(phenylmethyl) amides and can be used in place ofN-(12-methoxy-1-oxododecyl)-L-phenylalanine, 1,1-dimethyl ester withsubstantially similar antiviral results.

EXAMPLE 96

Various illustrative compounds synthesized above were tested forinhibition of HIV-1 in a test which measured reduction of cytopathogeniceffect in virus-infected syncytium-sensitive Leu-3 a-positive CEM cellsgrown in tissue culture as follows:

Tissue culture plates were incubated at 37° C. in a humidified, 5% CO₂atmosphere and observed microscopically for toxicity and/orcytopathogenic effect (CPE). At 1 hour prior to infection each testarticle was prepared from the frozen stock, and a 20 μl volume of eachdilution (prepared as a 10×concentration) was added to the appropriatewells of both infected and uninfected cells.

Assays were done in 96-well tissue culture plates. CEM cells weretreated with polybrene at a concentration of 2 μg/ml, and an 80 μlvolume of cells (1×10⁴ cells) was dispensed into each well. A 100 μlvolume of each test article dilution (prepared as a 2×concentration) wasadded to 5 wells of cells, and the cells were incubated at 37° C. for 1hour. A frozen culture of HIV-1, strain HTVL-III_(B), was diluted inculture medium to a concentration of 5×10⁴ TCID₅₀ per ml, and a 20 μlvolume (containing 10³ TCID₅₀ of virus) was added to 3 of the wells foreach test article concentration. This resulted in a multiplicity ofinfection of 0.1 for the HIV-1 infected samples. A 20 μl volume ofnormal culture medium was added to the remaining wells to allowevaluation of cytotoxicity. Each plate contained 6 wells of untreated,uninfected, cell control samples and 6 wells of untreated, infected,virus control samples.

On the 7th to 9th day post-infection, the cells in each well wereresuspended and a 100 μl sample of each cell suspension was removed foruse in an MTT assay. A 20 μl volume of a 5 mg/ml solution of3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide (MTT) wasadded to each 100 μl cell suspension, and the cells were incubated at37° C. in 5% CO₂ for 4 hours. During this incubation MTT ismetabolically reduced by living cells, resulting in the production of acolored formazan product. A 100 μl volume of a solution of 10% sodiumdodecyl sulfate in 0.01N hydrochloric acid was added to each sample, andthe samples were incubated overnight. The absorbance at 590 nm wasdetermined for each sample using a Molecular Devices V_(max) microplatereader. This assay detects drug-induced suppression of viral CPE, aswell as drug cytotoxicity, by measuring the generation of MTT-formazanby surviving cells.

The following Table I, below, set forth the test results of theforegoing assay for HIV inhibition by illustrative compounds prepared inthe foregoing examples.

                  TABLE I                                                         ______________________________________                                        HIV ACTIVITY OF FATTY ACID ANALOGS AND PRODRUGS                                              EC.sub.50                                                              Example #                                                                            (μM)                                                        ______________________________________                                                1      4.3                                                                    5      >430                                                                   6      >470                                                                   7      18.7                                                                   8      6.1                                                                    9      16.6                                                                   12     192                                                                    13     >400                                                                   14     3.8                                                                    15     >350                                                                   16     4.5                                                                    17     8.2                                                                    18     >285                                                                   19     >350                                                                   20     >310                                                                   21     8.6                                                                    22     >245                                                                   23     9.3                                                                    24     >260                                                                   25     >240                                                                   26     >300                                                                   28     >250                                                                   29     >315                                                                   30     6.1                                                                    31     24                                                                     34     >300                                                                   36     5.8                                                                    39     6.7                                                                    42     6.4                                                                    45     <2.7                                                                   48     >265                                                                   49     5.4                                                                    50     11.1                                                                   52     >245                                                                   54     >230                                                                   55     >240                                                                   56     >240                                                                   59     7.3                                                                    62     >205                                                                   65     7.4                                                                    68     13.1                                                                   71     18                                                                     74     >221                                                                   77     11.8                                                                   80     >225                                                                   81     27.5                                                                   82     13                                                                     83     >265                                                                   84     >470                                                                   85     >390                                                                   86A    >350                                                                   86B    >350                                                                   87A    >290                                                                   87B    >290                                                                   88     >450                                                                   89     >430                                                           ______________________________________                                    

EXAMPLE 97

Various illustrative compounds synthesized in Examples above were testedfor biological half-life. Compounds were incubated at a concentration ofapproximately 2 mcg/mL in a rat liver S9 preparation which was preparedaccording to standard procedures with minor modifications¹. Thereactions were conducted at 37° C. in a water bath and stopped by theaddition of ice cold methanol at various times ranging from 0 to 20minutes. Aliquots of the incubations were analyzed by high performanceliquid chromatography (HPLC) for the compound of interest. The analyseswere conducted on a Waters HPLC system consisting of a model 510 pumpand a Wisp model 712 automatic injector. Waters C18 columns were used toperform the separations. The compounds were detected by UV adsorption.The mobile phases consisted of acetonitrile and sodium phosphate buffer(40 mM, pH 3.5); specific conditions were varied slightly for eachcompound. Concentrations of each compound were determined with time andthe rate of metabolism was determined by analyzing the data using theCSTRIP program².

Table II, below, sets forth the biological half-life of theseillustrative compounds:

                  TABLE II                                                        ______________________________________                                        HALF-LIFE OF 12-METHOXYDODECANOIC ACID DERIVATIVES                            IN RAT HEPATIC S9 PREPARATION                                                 Example #    Half-life (Minutes)                                              49           1.07                                                             56           1.97                                                             18           8.46                                                             14           2.41                                                             68           8.54                                                             17           a                                                                ______________________________________                                         a = Not detected at initial sampling time (ca. 5 min.).                  

The antiviral agents described herein can be used for administration toa mammalian host infected with a lentivirus, e.g. visna virus or thehuman immunodeficiency virus, by conventional means, preferably informulations with pharmaceutically acceptable diluents and carriers.These agents can be used in the free amine form or in their salt form.Pharmaceutically acceptable salt derivatives are illustrated, forexample, by the HCl salt. The amount of the active agent to beadministered must be an effective amount, that is, an amount which ismedically beneficial but does not present toxic effects which overweighthe advantages which accompany its use. It would be expected that theadult human dosage would normally range upward from about one mg/kg/dayof the active compound and generally in a range of about 100 to 1000mg/kg/day. The preferable route of administration is orally in the formof capsules, tablets, syrups, elixirs and the like, although parenteraladministration also can be used. Suitable formulations of the activecompound in pharmaceutically acceptable diluents and carriers intherapeutic dosage from can be prepared by reference to general texts inthe field such as, for example, Remington's Pharmaceutical Sciences, Ed.Arthur Osol, 16th ed., 1980, Mack Publishing Co., Easton, Pa.

Various other examples will be apparent to the person skilled in the artafter reading the present disclosure without departing from the spiritand scope of the invention. It is intended that all such other examplesbe included within the scope of the appended claims.

What is claimed is:
 1. A compound of the formula ##STR96## wherein: FAis a heteroatom-containing fatty acid moiety selected from the groupconsisting of CH₃ O(CH₂)₁₁ -and CH₃ (CH₂)₉ O(CH₂)₂ -;X is selected fromthe group consisting of amido, monoalkyl-amido, dialkyl-amido,monoaryl-amido, monoaryl-amido substituted with OH or halogen,diaryl-amido, and diaryl-amido substituted with OH or halogen; and inwhich the number of carbon atoms in alkyl are from one to eight and thenumber of carbon atoms in aryl is six.
 2. A compound of claim 1 in whichFA is CH₃ O(CH₂)₁₁ -.
 3. A compound of claim 1 in which FA is CH₃ (CH₂)₉O(CH₂)₂ -.
 4. A compound of claim 1 in which X is NH₂.
 5. A compound ofclaim 1 in which X is NHBn.
 6. A compound of claim 1 in which X is NEt₂.7. A compound of claim 1 in which X is NHCH₂ CH₂ Ph.
 8. A compound ofclaim 1 in which X is ##STR97##
 9. A compound of claim 1 in which X is##STR98##
 10. A compound of claim 2 in which X is NH₂.
 11. A compound ofclaim 2 in which X is NHBn.
 12. A compound of claim 2 in which X isNEt₂.
 13. A compound of claim 2 in which X is NHCH₂ CH₂ Ph.
 14. Acompound of claim 2 in which X is ##STR99##
 15. A compound of claim 2 inwhich X is ##STR100##